US 2005O176680A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0176680 A1 Lalji et al. (43) Pub. Date: Aug. 11, 2005

(54) COMBINATION OF SEDATIVE AND A Publication Classification NEUROTRANSMITTER MODULATOR, AND METHODS FOR IMPROVING SLEEP (51) Int. Cl." ...... A61K 31/724; A61K 31/137; QUALITY AND TREATING DEPRESSION A61K 31/495 (52) U.S. Cl...... 514/58; 514/649; 514/469 (75) Inventors: Karim Lalji, Sudbury, MA (US); Timothy J. Barberich, Concord, MA (US); Judy Caron, Westwood, MA (57) ABSTRACT (US); Thomas Wessel, Lenox, MA (US) One aspect of the present invention relates to pharmaceutical compositions containing two or more active agents that Correspondence Address: when taken together can be used to treat, e.g., insomnia FOLEY HOAG, LLP and/or depression. The first component of the pharmaceuti PATENT GROUP, WORLD TRADE CENTER cal composition is a GABA receptor modulating compound. WEST The Second component of the pharmaceutical composition is 155 SEAPORT BLVD a Serotonin reuptake inhibitor, a norepinephrine reuptake BOSTON, MA 02110 (US) inhibitor, a 5-HTA modulator, or dopamine reuptake inhibi tor. In certain embodiments, the pharmaceutical composition (73) Assignee: Sepracor, Inc., Marlborough, MA (US) comprises eSZopiclone. In a preferred embodiment, the (21) Appl. No.: 11/007,795 pharmaceutical composition comprises eSZopiclone and flu oxetine. The present invention also relates to a method of (22) Filed: Dec. 8, 2004 treating a sleep abnormality, treating insomnia, treating depression, augmenting antidepressant therapy, eliciting a Related U.S. Application Data dose-sparing effect, reducing depression relapse, improving the efficacy of antidepressant therapy or improving the (60) Provisional application No. 60/529,156, filed on Dec. tolerability of antidepressant therapy, comprising co-admin 11, 2003. Provisional application No. 60/541,614, istering to a patient in need thereof a GABA-receptor filed on Feb. 4, 2004. Provisional application No. modulating compound; and a SRI, NRI, 5-HT modulator 60/633,213, filed on Dec. 3, 2004. or DRI Patent Application Publication Aug. 11, 2005 Sheet 1 of 16 US 2005/0176680 A1

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1. Please rate the current (last2 weeks) SEVERTY of your insomnia problem(s). Non

ed are you with your current sleep pattem? 2D 3. To whatejcient do you consider your sleep problem to NTERFERE with your daily functioning (e.g., daytime fatigue, ability fofunctionatworkdaily chores, concentration, memory, mood, etc)? Not at annerfering Very maring 4. How NOTICEABLE toothers doyotrikyoursleepingpremishtems of imping the quality of your?e Notatatinoticeable Attle somewhat .uch Very much noticeable or . . . 20 5. How WORREDDSTRESSED are you about your currentsleep problem? Attle 'Sonowhat 20 EEP currently (last two weeks)? ..fair sound 7. Howwould you rateyour general Exhauste Ve 8. To what exteridoyou consideryouroument seapproblems cause daytime FATGUE Notatal A little Somewhat . . ?uch . . .2 : 9. To what extendo you consider your current sleep problem the day because of ATTENTONICONCENTRATION problems? . . - Not at all interfering 10. Towhat existicesyour arrent from enjoying RELATIONSHIPS with others friends,Nota: co-workers)? squwn Very much interfering 2 . . . . 3 11. to prodice MOOD disturbances such as irritability tension, a MV . - - . . . Much Wory much

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COMBINATION OF SEDATIVE AND A the order of 8-50 hours) due to long terminal half-lives, and NEUROTRANSMITTER MODULATOR, AND have a well-known Spectrum of Side effects, including METHODS FOR IMPROVING SLEEP QUALITY lethargy, confusion, depression and next day hangover AND TREATING DEPRESSION effects. In addition, chronic use has been associated with a high potential for addiction involving both physical and RELATED APPLICATIONS psychological dependence. 0001. This application claims the benefit of priority to 0006 During the 1980s, the pharmaceutical treatment of U.S. Provisional Patent Application Ser. No. 60/529,156, insomnia shifted away from barbiturates and other CNS filed Dec. 11, 2003; and U.S. Provisional Patent Application depressants toward the benzodiazepine class of Sedative Ser. No. 60/541,614, filed Feb. 4, 2004; and U.S. Provisional hypnotic agents. This class of compounds produces a calm Patent Application Ser. No. 60/ , filed Dec. 3, 2004; ing effect that results in a sleep-like State in humans and the Specifications of each application are hereby incorpo animals, with a greater Safety margin than prior hypnotics. rated by reference. However, many benzodiazepines possess Side effects that limit their usefulness in certain patient populations. These BACKGROUND OF THE INVENTION problems include synergy with other CNS depressants 0002 Sleep is controlled by two biological processes, the (especially alcohol), the development of tolerance upon homeostatic drive and the circadian rythym. The homestatic repeat dosing, dependency, withdrawal, rebound insomnia drive manifests itself as an increased drive for sleep. This following discontinuation of dosing, hangover effects the drive for sleep accumulates acroSS the period of WakefulneSS next day and impairment of psychomotor performance and (typically daytime) and dissipates across the sleep period. memory. Next day Sleepiness and memory impairment, The circadian rhythm of Sleep-wake shows a biphasic curve which can include amnesia for events occurring prior to and with the greatest drive for Sleep occurring between midnight after drug administration, is of particular concern in the and 5 AM, and between 2 PM and 4 PM. It is believed that elderly whose cognitive functions may already be impaired major circadian influences are an alerting pulse in the by the aging process. evening and in the morning. It is the interaction of these 0007 More recent treatments for insomnia have used processes which give rise to the 24-hour sleep Schedule. For non-benzodiazepine compounds, which Show an improved individuals with a usual sleep period of 11 PM to 7 AM, Side effect profile over the benzodiazepine class of Sedative Sleep onset in the evening occurs primarily as a function of hypnotics. The first of these agents to be approved by the homeostatic drive. After about four hours of sleep (at about United States Food and Drug Administration (FDA) for 3 AM) homeostatic drive dissipates significantly and wake marketing in the United States was Zolpidem, marketed by fulneSS begins to intrude into the sleep period. This propen Sanofi-Synthelabo as AMBIENCR (Zolpidem tartrate), which sity to increased WakefulneSS is further increased by the rise is based on the imidazopyridine backbone (see U.S. Pat. in the circadian alerting pulse at about 5 AM. In terms of the Nos. 4,382,938 and 4,460,592). In addition to Zolpidem, pharmacological management of insomnia, two Vulnerabili Zaleplon, which is marketed by Jones Pharma as ties have been recognized. The first is difficulty initially SONATAF), was been approved by the FDA, Zaleplon is a falling asleep, with the Second being reawakening in the pyrazolopyrimidine-based compound (see U.S. Pat. No. middle of the night. 4,626.538). Other non-benzodiazepine compounds and/or 0003. Many physiological functions are characterized by methods for making or using the same have also been diurnal rhythms, in which levels of circulating hormones, reported (see, e.g., U.S. Pat. Nos. 4,794,185, 4,808,594, catecholamines and other compounds fluctuate during the 4,847.256, 5,714,607, 4,654,347; 5,538,977, 5,891.891). day and/or night. Certain medical disorders, Such as insom Attempts have also been disclosed to provide controlled nia, are associated with abnormalities in these rhythms. The release dosage forms, particularly in the context of Zolpidem time, within a 24 hour period, of administration of drugs for and salts thereof (see WO 00/33835 and EP 1005 863 A1). the prevention and treatment of Such disorders can be a 0008 Norepinephrine and serotonin are mammalian neu critical factor in determining efficacy of the therapy. rotransmitters that play important roles in a wide variety of 0004. The term “insomnia” refers to the perception of physiological processes. Norepinephrine, also called nora inadequate or non-restful sleep by a patient. Insomnia is a drenaline, is a neurotransmitter that doubles part-time as a frequent complaint, reported by 32% of the adult population hormone. As a neurotransmitter, norepinephrine helps to Surveyed in the Los Angeles area (Bixler et al, Amer. Journal regulate arousal, dreaming, and moods. AS a hormone, it acts of Psychiatry 136:1257-1262, 1979), and 13% of the popu to increase blood preSSure, constrict blood vessels and lation Surveyed in San Marino, Italy (Lugaresi et al., Psy increase heart rate-responses that occur when we feel chiatric Annals 17:446-453, 1987). Fully 45% of the sur StreSS. veyed adult population of Alachua County, Florida, reported 0009 Serotonin (5-hydroxytryptamine, 5-HT) is widely trouble getting to sleep or staying asleep (Karacan et al., distributed in animals and plants, occurring in Vertebrates, Social Science and Medicine 10:239-244, 1976). The preva fruits, nuts, and Venoms. A number of congeners of Serotonin lence of insomnia has also been shown to be related to the are also found in nature and have been shown to possess a age and Sex of the individuals, being more prevalent in older variety of peripheral and central nervous System activities. individuals, especially adults aged 65 and over, and in Serotonin may be obtained from a variety of dietary Sources, females. however, endogenous 5-HT is Synthesized from tryptophan 0005 Early treatments for insomnia commonly through the actions of the enzymes tryptophan hydroxylase employed central nervous System (CNS) depressants such as and aromatic L-amino acid decarboxylase. Both dietary and barbiturates. These compounds are typically long acting (on endogenous 5-HT are rapidly metabolized and inactivated US 2005/0176680 A1 Aug. 11, 2005 by monoamine oxidase and aldehyde dehydrogenase to the tically effective amount of a Sedative agent. In a preferred major metabolite, 5-hydroxyindoleacetic acid (5-HIAA). embodiment, the Sedative agent is eSZopiclone, or a phar 0.010 Serotonin is implicated in the etiology or treatment maceutically acceptable Salt, Solvate, clathrate, polymorph, of various disorders, particularly those of the central nervous or co-crystal thereof. The present invention also relates to a System, including anxiety, depression, obsessive-compul method for eliciting a dose-sparing effect in a patient under Sive disorder, Schizophrenia, Stroke, obesity, pain, hyperten going treatment with an antidepressant comprising admin Sion, Vascular disorders, migraine, and nausea. Recently, istering to the patient a therapeutically effective amount of understanding of the role of 5-HT in these and other disor a Sedative agent. In a preferred embodiment, the Sedative derS has advanced rapidly due to increasing understanding agent is eSZopiclone, or a pharmaceutically acceptable Salt, of the physiological role of various Serotonin receptor Sub Solvate, clathrate, polymorph, or co-crystal thereof. types. 0015. Furthermore, the present invention relates to a 0011 Neurotransmitters (NTS) produce their effects as a method for reducing depression relapse in a patient who consequence of interactions with cellular receptors. Neu received antidepressant treatment comprising administering rotransmitters, including Serotonin, are Synthesized in brain to the patient a therapeutically effective amount of a Sedative neurons and Stored in Vesicles. Upon a nerve impulse, they agent. In one embodiment, the Sedative agent is adminis are released into the Synaptic cleft, where they interact with tered chronically or long-term. In a preferred embodiment, various postsynaptic receptors. The actions of 5-HT are the Sedative agent is eSZopiclone, or a pharmaceutically terminated by three major mechanisms: diffusion; metabo acceptable Salt, Solvate, clathrate, polymorph, or co-crystal lism; and uptake back into the Synaptic cleft through the thereof. actions of Specific amine membrane transporter Systems. The major mechanism by which the action of Serotonin is BRIEF DESCRIPTION OF THE FIGURES terminated is by uptake through presynaptic membranes. 0016 FIG. 1 depicts a schematic diagram of a method for After 5-HT acts on its various postsynaptic receptors, it is preparing (S)-Zopiclone D-malate (IPC=in-process control removed from the Synaptic cleft back into the nerve terminal testing). through an uptake mechanism involving a specific mem brane transporter in a manner Similar to that of other 0017 FIG.2 depicts a schematic diagram of a method for biogenic amines. Thus, the actions of 5-HT, or any neu preparing (S)-Zopiclone as the free base (IPC=in-process rotransmitter, can be modulated by agents that: Stimulate or control testing). inhibit its biosynthesis, agents that block its Storage; agents 0018 FIG. 3 depicts a schematic diagram of a clinical that Stimulate or inhibit its release, agents that mimic or Study protocol used to assess the Safety and efficacy of inhibit its actions at its various postsynaptic receptors, compositions and methods of the present invention. agents that inhibit its reuptake into the nerve terminal; and agents that affect its metabolism. 0019 FIG. 4 depicts graphically fluoxetine titration as a function of length of treatment and co-administration with a 0012. Accordingly, there is a need in the art for serotonin placebo or eSZopiclone. reuptake inhibitor-Sedative, norepinephrine reuptake inhibi tor-Sedative, 5-HT2A modulator-Sedative, and dopamine 0020 FIG. 5 depicts graphically Subjective Wake Time reuptake inhibitor-Sedative compositions that induce and After Sleep Onset (WASO) as a function of length of maintain Sleep as Single dose nocturnal formulations, but treatment with a placebo or eSZopiclone. without the Side effects associated with the longer-acting 0021 FIG. 6 depicts a chart of Subjective Sleep Latency hypnotics. The present invention fulfills this need and fur (SL) as a function of length of treatment with a placebo or ther provides other related advantages. eSZopiclone. SUMMARY OF THE INVENTION 0022 FIG. 7 depicts a chart of Subjective Total Sleep Time (TST) as a function of length of treatment with a 0013 The present invention generally relates to pharma placebo or eSZopiclone. ceutical compositions comprising a Sedative agent, and an antidepressant, including without limitation Serotonin 0023 FIG. 8 depicts a chart of improvement from base reuptake inhibitors, norepinephrine reuptake inhibitors, line in Ham-D-17 as a function of length of treatment with dopamine reuptake inhibitors, CRS antagonists and 5-HT2A a placebo or eSZopiclone. receptor modulators. The Sedative agent is a GABA receptor 0024 FIG. 9 depicts a chart of improvement from base modulating compound. In a preferred embodiment, the line in Ham-D-17 (excluding questions related to insomnia) Sedative agent is eSZopiclone, or a pharmaceutically accept as a function of length of treatment with a placebo or able Salt, Solvate, clathrate, polymorph, or co-crystal thereof. eSZopiclone. The pharmaceutical compositions of the invention are useful in the treatment of various sleep disorders. In addition, the 0025 FIG. 10 depicts a chart of improvement from present invention also relates to a method of treating a baseline in Clinical Global Impression (Severity) as a func patient Suffering from a Sleep abnormality, insomnia, or tion of length of treatment with a placebo or eSZopiclone. depression comprising administering a therapeutically effec 0026 FIG. 11 depicts a chart of Clinical Global Impres tive amount of a pharmaceutical composition of the inven Sion (Global Improvement) as a function of length of tion. treatment with a placebo or eSZopiclone. 0.014. In addition, the present invention relates to a 0027 FIG. 12 depicts a graph of Time to Onset of 50% method for augmentation of antidepressant therapy in a Antidepressant Response on HAM-D6 (Maier) Scores as a patient comprising administering to the patient a therapeu function of treatment with a placebo or eSZopiclone. US 2005/0176680 A1 Aug. 11, 2005

0028 FIG. 13 depicts a graph of Time to Onset of 30% fluxetine, or a pharmaceutically acceptable Salt, Solvate, Antidepressant Response on HAM-D6 (Maier) Scores as a clathrate, polymorph, or co-crystal of any one or both of function of treatment with a placebo or eSZopiclone. them. 0029 FIG. 14 depicts an Insomnia Severity Index (ISI) 0034. In another embodiment, the present invention questionnaire used in the clinical-study protocol to assess relates to a method for augmentation of antidepressant the Safety and efficacy of compositions and methods of the therapy in a patient comprising administering to the patient present invention. a therapeutically effective amount of a Sedative agent. In a 0030 FIG. 15 depicts a portion of an Acute Health preferred embodiment, the Sedative agent is eSZopiclone, or Survey questionnaire used in the clinical-study protocol to a pharmaceutically acceptable Salt, Solvate, clathrate, poly assess the Safety and efficacy of compositions and methods morph, or co-crystal thereof. of the present invention. 0035. The present invention also relates to a method for eliciting a dose-sparing effect in a patient undergoing treat 0031 FIG. 16 depicts a portion of an Acute Health ment with an antidepressant comprising administering to the Survey questionnaire used in the clinical-study protocol to patient a therapeutically effective amount of a Sedative assess the Safety and efficacy of compositions and methods agent. In a preferred embodiment, the Sedative agent is of the present invention. eSZopiclone, or a pharmaceutically acceptable Salt, Solvate, DETAILED DESCRIPTION OF THE clathrate, polymorph, or co-crystal thereof. INVENTION 0036 Furthermore, the present invention relates to a method for reducing depression relapse in a patient who 0.032 The present invention relates generally to pharma received antidepressant treatment comprising administering ceutical compositions containing two or more active agents to the patient a therapeutically effective amount of a Sedative that when taken together improve the quality of Sleep for a agent. In one embodiment, the Sedative agent is adminis patient. In certain embodiments, the present invention tered chronically or long-term. In a preferred embodiment, relates to a pharmaceutical composition comprising an anti the Sedative agent is eSZopiclone, or a pharmaceutically depressent and a Sedative agent. In certain embodiments, the acceptable Salt, Solvate, clathrate, polymorph, or co-crystal present invention relates to a pharmaceutical composition thereof. comprising a Serotonin reuptake inhibitor and a Sedative agent. In certain embodiments, the present invention relates 0037) Sleep Difficulties and Insomnia to a pharmaceutical composition comprising a NRI and a 0038. Several epidemiologic studies suggest that 10% to Sedative agent. In certain embodiments, the present inven 15% of adults suffer from chronic insomnia, and an addi tion relates to a pharmaceutical composition comprising a tional 25% to 35% have transient or occasional insomnia 5-HT modulator and a sedative agent. In certain embodi ments, the present invention relates to a pharmaceutical (Roth T. Int. J. Clin. Pract. Suppl. 2001,3-8). composition comprising a dopamine reuptake inhibitor and 0039. The National Sleep Foundation's 2002 Sleep in a Sedative agent. The Sedative agent is a GABA receptor America Survey assessed the occurrence of four Symptoms modulating compound. In a preferred embodiment, the of insomnia in adults in the United States: difficulty falling Sedative agent is eSZopiclone, or a pharmaceutically accept asleep, waking a lot during the night, waking up too early able Salt, Solvate, clatherate, polymorph, or co-crystal and not being able to get back to Sleep; and waking up thereof Another aspect of the present invention relates to a feeling unrefreshed. In the Survey, 58% of the respondents method of treating a patient Suffering from a sleep disorder reported experiencing at least one of these Symptoms a few comprising the Step of administering to Said patient a nights a week or more, and 35% reported difficulties every therapeutically effective dose of a pharmaceutical composi night or almost every night within the past year (National tion containing two or more active agents that when taken Sleep Foundation. 2002 Sleep in America Poll. Washington, together improve the quality of Sleep or Sleep disorders for DC: WB & A Market Research, 2002,1-43). In addition, of Said patient. Another aspect of the present invention relates those reporting insomnia Symptoms at least a few nights a to a method of treating a patient Suffering from depression week, 40% reported feeling unrefreshed upon awakening, comprising the Step of administering to Said patient a 36% reported being awake a lot during the night, 25% therapeutically effective dose of a pharmaceutical composi reported difficulty falling asleep, and 24% reported waking tion of the invention. up too early and being unable to fall back asleep. 0033. In certain embodiments, said pharmaceutical com 0040. The major types of insomnia are often described as position comprises a Serotonin reuptake inhibitor and a primary and Secondary insomnia (as in the American Psy Sedative agent. In certain embodiments, Said pharmaceutical chiatric ASSociation's Diagnostic and Statistical Manual of composition comprises a norepinephrine reuptake inhibitor Mental Disorders, Text Revision. 4th ed. Washington, DC: and a Sedative agent. In certain embodiments, Said pharma American Psychiatric Publishing, Inc., 2000 DSM), ceutical composition comprises a 5-HTA modulator and a chronic versus acute/transient insomnia, intrinsic verSuS Sedative agent. In certain embodiments, Said pharmaceutical extrinsic insomnia (as in the International Classification of composition comprises a dopamine reuptake inhibitor and a Sleep Disorders ICSD), and sleep-onset versus sleep main Sedative agent. In a preferred embodiment, the Sedative is tenance (Diagnostic Classification Steering Committee. eSZopiclone, or a pharmaceutically acceptable Salt, Solvate, International Classification of Sleep Disorders (ICSD): clathrate, polymorph, or co-crystal thereof. In another Diagnostic and Coding Manual. Rochester, Minn.: Ameri embodiment, Said pharmaceutical composition comprises can Sleep Disorders Association, 1990). Many patients with eSZopiclone and a SRI. In yet another embodiment, Said sleep disturbance will fall into more than one of these pharmaceutical composition comprises eSZopiclone and categories or will have unspecified dissatisfaction with the US 2005/0176680 A1 Aug. 11, 2005 quality of their sleep (Roth T. Int. J. Clin. Pract. Suppl. abnormal function of the catecholamine (primarily norepi 2001,3-8). The fourth edition of the DSM (DSM-IV) defines nephrine) and/or serotonin transmitter Systems. In this insomnia as difficulties in Sleep onset (or initiation), diffi hypothesis, most forms of depression are associated with a culties in Sleep maintenance, or Sleep that is non restorative. deficiency of norepinephrine and/or Serotonin at function ally important adrenergic or Serotonergic receptors. Hence 0041 Chronic insomnia may result from several different drugs that enhance the concentrations of norepinephrine sources (Rajput et al., Am. Fam. Physician, 1999, 60:1431 (NE) and/or serotonin at these receptors should alleviate to 1438). Patients with chronic insomnia can often have several an extent the Symptoms of depression. Approaches to the Sleep complaints simultaneously and experience a range of treatment of depression over the years have involved the use Sleep disturbances, including prolonged latency to Sleep of agents (stimulants) that mimic norepinephrine, agents onset, increased time awake during the Sleep period, and (MAOIs) that increase the levels of NE and 5-HT by reduced total sleep time (Benca R M, J. Clin. Psychiatry, inhibiting their metabolism; and drugs that increase these 2001, 62 Suppl 10:33-38). levels at the receptor by inhibiting the uptake of NE and 0.042 Sleep maintenance problems may take several 5-HT. forms, including frequent awakenings, an increase in time spent awake after initially falling asleep (wake time after 0048. The classical tricyclic antidepressants (TCAS) cur sleep onset, or WASO, which is a robust measure of sleep rently available block primarily the uptake of norepineph maintenance), sleep fragmentation (transient microarousals rine and also, to varying degrees, the uptake of 5-HT appearing on an EEG but not necessarily involving fill depending on whether they are Secondary or tertiary amines. wakefulness), and unrefreshing sleep. Of these, WASO is a Tertiary amines Such as imipramine and amitriptyline are particularly sensitive measure of sleep improvement. WASO more selective inhibitors of 5-HT than catecholamines, may include a number of microarousals, as well as all compared with Secondary amines Such as desipramine. More periods of fill wakefulness, and thus increases in WASO of recently, selective 5-HT reuptake inhibitors (SSRIs) have only a few minutes may be indicative of Substantially been investigated as potential antidepressants with the improved Sleep continuity. anticipation that these agents, unlike the first-generation TCAS, would-possess fewer Side effects, Such as anticho 0043. The severity of insomnia can be directly correlated linergic actions and cardiotoxicity, and would be leSS likely to Severity of next-day functional impairment. There is also to cause Sedation and weight gain. Strong evidence that, compared with patients without insom nia, patients with chronic insomnia experience a Subjective 0049. Three selective 5-HT uptake inhibitors, also deterioration in waking behaviors and psychoSocial func referred to as Second-generation antidepressants, have been tioning, including impaired memory, concentration, ability introduced to the U.S. market. Fluoxetine (PROZAC(R), to accomplish tasks, and enjoyment of interpersonal rela sertraline (ZOLOFT(R), and paroxetine (PAXIL(R) have tionships (Roth et al., Sleep, 1999, 22 Suppl 2:S354-S358). gained immediate acceptance, each appearing in recent listings of the top 200 prescription drugs. Fluoxetine was 0044 Sleep maintenance problems may cause decreases approved also for the treatment of obsessive-compulsive in next-day functioning. Bonnet Studied healthy Volunteers disorder. These agents do not appear to possess greater with normal sleep habits and found that, with increasing efficacy than the TCAS, nor do they generally possess a periods of induced arousal or insomnia during the night, faster onset of action; however, they do have the advantage residual effects of next-day performance on evaluations of of a lower side-effect profile. Of these three SSRIs, parox Vigilance, reaction time, Sleepiness, and other measures etine is the most potent inhibitor of 5-HT uptake, fluoxetine experienced corresponding decreases (Bonnet M H, Physiol. the least. Sertaline is the most selective for 5-HT versus NE Behav, 1989, 45:1049-1055). uptake, fluoxetine the least Selective. Fluoxetine and Sertra 0045 Depression line produce active metabolites, while paroxetine is metabo lized to inactive metabolites. The SSRIs, in general, affect 0046) Psychiatric disorders are pathological conditions of only the uptake of Serotonin and display little or no affinity the brain characterized by identifiable symptoms that result for various receptor Systems including muscarinic, adrener in abnormalities in cognition, emotion or mood, or the gic, dopamine, histamine, or 5-HT receptors. highest integrative aspects of behavior. These disorders may vary in Severity of Symptoms, duration, and functional 0050 Venlafaxine (EFFEXOR(R) is a recently introduced impairment. Psychiatric disorders afflict millions of people antidepressant, differing from the classical TCAS and the Worldwide resulting in tremendous human Suffering and SSRIs chemically and pharmacologically in that it acts as a economic burden due to lost productivity. Mood disorders potent inhibitor of both 5-HT and norepinephrine uptake, as are a type of psychiatric disorder often defined as a group of well as weakly inhibiting dopamine uptake. Its major heterogeneous, typically recurrent illnesses including uni metabolite, O-desmethylvenlafaxine, Shares a similar pro polar (depressive) and bipolar (manic-depressive) disorders file. Neither venlafaxine nor its major metabolite have characterized by pervasive mood disturbances, psychomotor Significant affinity for muscarinic, histaminergic, benzodi dysfunction, and vegetative Symptoms. Suicide, the most aZephine, mu opioid, or adrenergic alpha-1 receptors. It is Serious complication in patients with mood disorders, is the administered as a racemic mixture. Both enantiomers inhibit cause of death in 15 to 25% of untreated patients with mood 5-HT and NE uptake, but the (S)(+)-isomer is more selective disorders, unrecognized or inadequately treated depression for 5-HT uptake. Venlafaxine possesses an efficacy equiva contributes to 50 to 70% of all completed Suicides. lent to that of the TCAS, and a benign side effect profile similar to those of the SSRIs. 0047 Depression is an affective disorder, the pathogen esis of which cannot be explained by any Single cause or 0051. Unfortunately, treatment options for depressed theory. The most widely accepted hypothesis involves patients who have Suboptimal clinical responses to therapy US 2005/0176680 A1 Aug. 11, 2005

With an antidepressant are limited. Approximately thirty 0058 Citalopram percent (30%) of patients initiating antidepressant therapy 0059) Citalopram is a selective, centrally acting serotonin show Suboptimal or delayed clinical responses to the first reuptake inhibitor having antidepressant activities. The anti line antidepressant agents that are commonly used to treat depressant activity of the compound has been reported in depression. Several publications, e.g., J. Hyttel Prog. Neuro-Psy 0.052 Typically, if a patient exhibits suboptimal or chopharniacol. & Biol. Psychiat. 1982, 6, 277-295; and A. delayed clinical response after several weeks of therapy with Gravem Acta Psychiatr. Scand. 1987, 75, 478-486. The an antidepressant, the clinician's initial approach is to compound has further been disclosed to show effects in the increase the dose of the antidepressant. If the patient's treatment of dementia and cerebrovascular disorders. See response remains unsatisfactory after increasing the dose, EP-A 474580. Christensen et al. reported on the pharmacol the most common approaches that many clinicians will ogy of citalopram in Eur: J. Pharmacol. 1977, 41, 153. pursue are: a) Switching to another antidepressant; or b) Others have described the clinical effectiveness of citalo adding a Second antidepressant; or c) attempting an aug pram, e.g., Dufour et al. Int. Clin. Psychopharmacol. 1987, mentation therapy by administering agents such as lithium 2, 225; and Timmerman et al., ibid., 239. In certain carbonate, thyroid hormone (triiodothyronine), psycho instances, citalopram is administered in the form of its Stimulants, modafinil, atypical antipsychotics, buspirone, or hydrobromide salt marketed under the name Cipralmil. pindolol. 0060 Citalopram has the chemical name 1-3-(dimethy 0053. There are very important, fundamental differences lamino)propyl)-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzo in these three approaches. The first involves switching the furan carbonitrile. Citalopram was first disclosed in DE patient to another antidepressant agent that may have dif 2,657,271 and U.S. Pat. No. 4,136,193. The structure of ferent pharmacodynamic and pharmacokinetic characteris citalopram is presented below. tics from the first agent. The Second attempts to utilize an antidepressant agent that will produce Synergistic effects With the first agent. Lastly, the third approach relies on NC potential augmentation of the concurrently administered original antidepressant by agents that in and of themselves may have limited or no direct antidepressant effect. 0054) The pharmacological mechanism of action for any of the commonly used augmentation agents described above and in the literature is not established, and data from controlled clinical trials to Support the use of these and other agents to bring about an augmentation of antidepressant F treatment is sparse. The most thoroughly researched agents that are utilized in many patients with antidepressant-resis 0061) The size of a prophylactic or therapeutic dose of tant depression are lithium and thyroid hormone. Several citalopram in the acute or chronic management of disease clinical trials with these two agents have shown that aug will vary with the severity of the condition to be treated and mentation with lithium or thyroid hormone is effective. the route of administration. The dose, and perhaps the dose 0055 Less reliable information in the literature suggests frequency, will also vary according to the age, body weight, that central nervous System Stimulants may also produce an and response of the individual patient. In general, the total augmentation effect in antidepressant therapy, but there is daily dose ranges, for the conditions described herein, is concern that these agents can produce tolerance and put the from about 1 mg to about 80 mg. Preferably, a daily dose patient at risk for physical and psychological dependence range should be between about 5 mg to about 50 mg. Most and possible drug abuse. Some clinicians utilize atypical preferably, a daily dose range should be between about 10 antipsychotics at low doses and buspirone which are gen mg to about 30 mg. In certain embodiments, a daily dosage erally well tolerated and may have additional utility in of 15, 20, or 25 mg may be preferred depending upon patient treating concomitant anxiety in depressed patients that are response. In managing the patient, the therapy may be refractory to their antidepressants. Pindolol has also been initiated at a lower dose, perhaps about 4 mg to about 6 mg shown to accelerate clinical responses in Some but not all and increased up to about 10 mg or higher depending-on the clinical studies reported. patient's global response. It may be necessary to use dosages 0056) Serotonin Reuptake Inhibitors (SRI) outside these ranges in Some cases. 0057. In general, a dose of an SRI or a pharmaceutically 0062) Duloxetine (CYMBALTA®) acceptable Salt thereof Suitable for administration to a 0063 Duloxetine is an antidepressant that functions by human will be in the range of 0.01 to 50 mg per kilogram inhibiting the reuptake of Serotonin and norepinephrine. body weight of the recipient per day, preferably in the range Duloxetine has the chemical name N-methyl-3-(1-naphtha of 0.1 to 3 mg per kilogram body weight per day. Unless lenyloxy)-3-(2-thienyl)propanamine and is usually adminis otherwise Stated all weights of active ingredients are calcu tered as the hydrochloride Salt. In certain instances, dulox lated in terms of drug per se. In certain embodiments, the etine is administered as the (+) enantiomer. The word desired dose is presented as two, three, four, five or more “dulloxetine” will be used here to refer to any acid addition Sub-doses administered at appropriate intervals throughout Salt or the free base of the molecule. Duloxetine was first the day. These Sub-doses may be administered in unit dosage taught by U.S. Pat. No. 4,956,388, which discloses its high forms, for example, containing about 5 to 50 mg. potency. Duloxetine is generally administered orally in the US 2005/0176680 A1 Aug. 11, 2005

form of a tablet or a capsule full of enteric coated granules. the route of administration. The dose, and perhaps the dose The chemical structure of dulloxetine is given below. frequency, will also vary according to the age, body weight, and response of the individual patient. In general, the total daily dose ranges, for the conditions described herein, is N1 from about 1 mg to about 80 mg. Preferably, a daily dose H range should be between about 5 mg to about 50 mg. Most preferably, a daily dose range should be between about 10 mg to about 30 mg. In certain embodiments, a daily dosage Y-> of 15, 20, or 25 mg may be preferred depending upon patient response. In managing the patient, the therapy may be initiated at a lower dose, perhaps about 4 mg to about 6 mg and increased up to about 10 mg or higher depending on the patient's global response. In elderly patients, a 10 mg dosage may be optimal. It may be necessary to use dosages outside 0064. The size of a prophylactic or therapeutic dose of these ranges in Some cases. dulloxetine in the acute or chronic management of disease 0069 Fluoxetine will vary with the severity of the condition to be treated and the route of administration. The dose, and perhaps the dose 0070 Fluoxetine is a potent, highly selective reuptake frequency, will also vary according to the age, body weight, inhibitor of Serotonin and is indicated for the treatment of and response of the individual patient. In general, the total depression and obsessions and compulsions related to obses daily dose ranges, for the conditions described herein, is sive-compulsive disorder (OCD). The use of fluoxetine for from about 1 mg to about 150 mg. Preferably, a daily dose indications other than treating depression is also disclosed in range should be between about 5 mg to about 80 mg. Most the following: U.S. Pat. Nos. 4,594,358, 4,647,591, 4,683, preferably, a daily dose range should be between about 5 mg 235, 4,940,585, 4,999,382, 5,151,448, 5,356,934, 5,446,070, to about 50 mg. In certain embodiments, a daily dosage of 5,589,511, and PCT Application WO 92/18005. The anti 10, 20, or 30 mg may be preferred depending upon patient depressant action of fluoxetine appears to be based on its response. In managing the patient, the therapy may be capacity to Selectively inhibit the uptake of Serotonin by the initiated at a lower dose, perhaps about 4 mg to about 6 mg neurons of the central nervous System. and increased up to about 10 mg or higher depending-on the patient's global response. It may be necessary to use dosages 0.071) Fluoxetine is described in U.S. Pat. No. 4,314,081 and has the chemical name N-methyl-3-(p-trifluorimeth outside these ranges in Some cases. ylphenoxy)3-phenylpropylamine. Fluoxetine is generally 0065 Escitalopram marketed as the racemic mixture of its two enantiomers in 0.066 Escitalopram is the S-enantiomer of citalopram. the form of a hydrochloride salt under the name Prozac. Escitalopram is greater than 100 times more potent in Fluoxetine hydrochloride is a white crystalline solid inhibiting Serotonin reuptake compared to the R-enantiomer. (molecular weight 345.79 g/mol) that has a solubility of 14 Escitalopram does significantly affect reuptake of norepi mg/mL in water. Other methods for the production of nephrine or dopamine. In addition, escitalopram has negli fluoxetine and new intermediates are disclosed in U.S. Pat. gible affinity for the adrenergic, dopamine (Ds), histamine No. 5,225,585. The chemical structure of fluoxetine hydro (H), muscarinic (Ms), and benzodiazepine receptors. chloride is shown below: Generally, escitalopram is administered as its oxalate Salt under the name LEXAPROTM. OCI 0067. Escitalopram has the chemical name (S)-(+)-1-3- FC O (dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydro-5- 3 N isobenzofuran carbonitrile oxalate. Citalopram was first disclosed in DE 2,657,271, corresponding to U.S. Pat No. 4,136,193. The structure of citalopram is presented below.

0072 The oral administration of fluoxetine in the treat ment of depression is often initiated with a 20 mg/day dose administered in the morning. If no improvement is observed over Several weeks, the dosage may be increased, though generally to no more than 80 mg/day. Doses above 20 mg/day are often administered once a day in the morning or by a b.i.d. Schedule (morning and noon). Following oral administration of fluoxetine hydrochloride (PROZAC(R) in 10 mg or 20 mg daily doses, fluoxetine hydrochloride has an elimination half-life of from 1-9 days, averaging about 2-3 0068 The size of a prophylactic or therapeutic dose of days. Additional product information, including dosage and escitalopram in the acute or chronic management of disease administration, can be found in the Physicians' Desk Ref will vary with the severity of the condition to be treated and erence, 48th Edition, 1994, pp. 877-880. US 2005/0176680 A1 Aug. 11, 2005

0.073 Although fluoxetine is generally marketed as the daily dose ranges, for the conditions described herein, is racemic mixture, Robertson et al., J. Med. Chem. 1988, 31, from about 1 mg to about 600 mg. Preferably, a daily dose 1412, taught the Separation of the R- and S-enantiomers of range should be between about 10 mg to about 300 mg. Most fluoxetine and showed that their activity as Serotonin uptake preferably, a daily dose range should be between about 50 inhibitors is similar to each other. Additionally, U.S. Pat. No. mg to about 200 mg. In certain embodiments, a daily dosage 5,104,899 discloses a method of treating depression in a of 75, 100, 125, or 150 mg may be preferred depending upon human patient comprising administering the S-(+)-enanti patient response. In managing the patient, the therapy may omer of fluoxetine in substantially optically pure form. PCT be initiated at a lower dose, perhaps about 20 mg to about application WO95/28152 discloses methods for treating or 25 mg and increased up to about 50 mg or higher depending improving memory, and for treating Sexual dysfunction. on the patient's global response. It may be necessary to use dosages outside these ranges in Some cases. In instances 0.074 The size of a prophylactic or therapeutic dose of where the dosage is greater than 100 mg per day, the total fluoxetine in the acute or chronic management of disease dosage may need to be administered in two separate doses. will vary with the severity of the condition to be treated and A reduced dosage may be required for In elderly patients or the route of administration. The dose, and perhaps the dose patients suffering from liver conditions. Children of 8-17 frequency, will also vary according to the age, body weight, years of age should be given a Starting dose of 25 mg. In and response of the individual patient. In general, the total certain instances, young girls may need to be given a lower daily dose ranges, for the conditions described herein, is dosage than boys of Similar age. from about 1 mg to about 150 mg. Preferably, a daily dose range should be between about 5 mg to about 80 mg. Most 0078 Milnacipran preferably, a daily dose range should be between about 10 mg to about 20 mg. In certain embodiments, a daily dosage 0079 Milnacipran is a inhibitor of serotonin and norepi of 30, 40, or 60 mg may be preferred depending upon patient nephrine reuptake which is used to treat depression. Mil response. In managing the patient, the therapy may be nacipran is also known in the art as F2207, TN-912, dal initiated at a lower dose, perhaps about 4 mg to about 8 mg cipran, midalcipran, and midalipran. The NE:5-HT and increased up to about 10 mg or higher depending-on the selectivity of milnacipran is 2:1. See Moret et al. Neurop patient's global response. It may be necessary to use dosages harmacology 1985, 24, 1211-1219 and Palmier et al. Eur: J. Clin. Pharmacol. 1989, 3, 235-238. Quite significantly, outside these ranges in Some cases. milnacipran has been used as an antidepressant in approxi 0075 Fluvoxamine mately 400,000 patients, and is known to be non-toxic in humans. Milnacipran was well tolerated and usually pro 0.076 Fluvoxamine is an inhibitor of serotonin reuptake duced no more adverse effects than placebo in clinical trials that is used to treat depression and obsessive-compulsive at dosages of 100 mg/day or 200 mg/day (Spencer and Wilde disorder. Fluvoxamine is described in U.S. Pat. No. 4,085, Drugs 1998, 56, 405-427). 225 and Neth. U.S. Pat. No. 7,503,310. The therapeutic activity of fluvoxamine has been described by Claassen et al. 0080 Milnacipran has the chemical name (N,N-diethyl in Brit. J. Pharmacol. 1977, 60, 505; De Wilde et al. in J. 2-aminomethyl-1-phenylcyclo-propanecarboxamide). Pro Affective Disord. 1982, 4, 249; and Benfield et al. in Drugs cedures for the preparation of Milnacipran are given U.S. 1986, 32, 313. The efficacy of fluvoxamine has been estab Pat. No. 4,478,836. The pharmacological activity of Mil lished for obsessive-compulsive outpatients in double-blind, nacipran is described by Moret and coworkers in Neurop placebo-controlled clinical trials. However, the utility of harmacology 1985, 24, 1211-19. Additional information fluvoxamine for long-term care lasting longer than 10 weeks regarding milnacipran may be found in the Merck Index, has not been evaluated in controlled trials. In certain 12 Edition, at entry 6281. The structure of Milnacipran is instances, fluvoxamine is administered in form of its maleate presented below. Salt under the name LuVOX. LuVOX is a crystalline Solid that melts at 120-121.5 C. The chemical name of fluvoxamine is 5-methoxy-1-4-(trifluoromethyl)-phenyl-1-pentanone EtN NH2 O-(2-aminoethyl)oxime and the structure is presented below.

0081. Those of skill in the art will recognize that com FC pounds Such as milnacipran may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomer ism and/or optical isomerism. It should be understood that 0077. The size of a prophylactic or therapeutic dose of the invention encompasses any tautomeric, conformational fluvoxamine in the acute or chronic management of disease isomeric, optical isomeric and/or geometric isomeric forms will vary with the severity of the condition to be treated and of the NE 5-HTSNRI compounds having one or more of the the route of administration. The dose, and perhaps the dose utilities described herein, as well as mixtures of these frequency, will also vary according to the age, body weight, various different forms. For example, as is clear from the and response of the individual patient. In general, the total above Structural diagram, milnacipran is optically active. It US 2005/0176680 A1 Aug. 11, 2005 has been reported in the literature that the dextrogyral enantiomer of milnacipran is about twice as active in inhib iting norepinephrine and Serotonin reuptake than the racemic F mixture, and that the levrogyral enantiomer is much leSS potent (see, Spencer and Wilde, 1998, Supra; Viazzo et al. Tetrahedron Lett. 1996, 37,4519-4522; Deprez et al. Eur: J. p-\ Drug Metab. Pharmacokinet. 1998, 23, 166-171). Accord O ingly, milnacipran may be administered in entantiomerically pure form (e.g., the pure dextrogyral enantiomer) or as a mixture of dextogyral and leVrogyral enantiomers, Such as a W w YaO racemic mixture. Unless Specifically noted otherwise, the term “milancipran' as used herein refers to both enantio N merically pure forms of milnacipran as well as to mixtures H of milnacipran enantiomers. Methods for Separating and HCI isolating the dextro- and levrogyral enantiomers of mil nacipran and other NE 5-HTSNRI compounds are well known (see Grard et al. Electrophoresis 2000, 21, 3028 0.086 U.S. Pat. No. 5,874.447 describes paroxetine sul 3034). fonate Salts, including paroxetine methane Sulfonate also 0082 The size of a prophylactic or therapeutic dose of known as paroxetine meSylate. These Sulfonate Salts have millancipran in the acute or chronic management of disease advantageous properties in comparison to the known Salts, will vary with the severity of the condition to be treated and including the hydrochloride Salts. For example, the Sulfonate the route of administration. The dose, and perhaps the dose Salts have high water Solubility and good thermal Stability, frequency, will also vary according to the age, body weight, making them useful in forming a commercial paroxetine and response of the individual patient. In general, the total dosage form. The U.S. Pat. No.5,874,447 patent discloses daily dose ranges, for the conditions described herein, is that tablets can be made by any known method including a from about 1 mg to about 400 mg. Preferably, a daily dose dry technique (direct compression, dry granulation) or a wet range should be between about 50 mg to about 250 mg. Most technique (wet granulation). preferably, a daily dose range should be between about 100 mg to about 200 mg. In certain embodiments, a daily dosage 0087. The size of a prophylactic or therapeutic dose of of 110, 130, 150, or 170 mg may be preferred depending paroxetine in the acute or chronic management of disease upon patient response. In managing the patient, the therapy will vary with the severity of the condition to be treated and may be initiated at a lower dose, perhaps about 20 mg to the route of administration. The dose, and perhaps the dose about 30 mg and increased up to about 50 mg or higher frequency, will also vary according to the age, body weight, depending-on the patient's global response. It may be nec and response of the individual patient. In general, the total essary to use dosages outside these ranges in Some cases. daily dose ranges, for the conditions described herein, is from about 1 mg to about 90 mg. Preferably, a daily dose 0083) Paroxetine range should be between about 5 mg to about 50 mg. Most 0084 Paroxetine is phenylpiperidine compound used to preferably, a daily dose range should be between about 10 treat major depressive disorder, Social anxiety disorder, mg to about 40 mg. In certain embodiments, a daily dosage obsessive compulsive disorder, panic disorder, generalized of 15, 20, or 30 mg may be preferred depending upon patient anxiety disorder, and posttraumatic StreSS disorder. The response. In managing the patient, the therapy may be therapeutic properties of paroxetine are attributed to inhibi initiated at a lower dose, perhaps about 4 mg to about 8 mg tion of neuronal reuptake of Serotonin. Paroxetine is gener and increased up to about 10 mg or higher depending-on the ally marketed as the hydrochloride Salt under the name patient's global response. It may be necessary to use dosages PAXIL(R). Paroxetine is reported in U.S. Pat. Nos. 3,912,743 outside these-ranges in Some cases. and 4,007,196 while the activity profile of the drug is given 0088 Sertraline in Lassen et al. Eur: J. Pharmacol. 1978, 47,351; Hassan et al. Brit. J. Clin. Pharmacol. 1985, 19, 705; Laursen et al. 0089. Sertraline is a serotonin reuptake inhibitor which is Acta Psychiat. Scand. 1985, 71, 249; and Battegay et al. marketed as an antidepressant. It is disclosed by U.S. Pat. Neuropsychobiology 1985, 13, 31. Dosage forms include No.4,536,518. The therapeutic effect of Sertraline is attrib immediate release tablets, extended release tablets, capsules uted to inhibition of CNS neuronal uptake of serotonin. and Suspensions. The active Substance in the commercial Clinical Studies in man indicate that Sertraline blocks the forms has been paroxetine hydrochloride and Specifically uptake of Serotonin in human platelets. In addition, in Vitro with regard to tablets and other solid forms the active Studies indicate that it is a very poor inhibitor of norepi ingredient has been paroxetine hydrochloride hemihydrate nephrine and dopamine neuronal uptake. Sertraline is a as described in U.S. Pat. No. 4,721,723 and EP 223403. naphthaleneamine that is generally marketed as the hydro chloride Salt under the brand name ZOLOFTE). 0085 Paroxetine hydrochloride is an off-white powder that has the chemical name (-)-trans 4R-(4'-fluorophenyl)- 0090 Sertraline hydrochloride has the molecular formula 3S-(3'4'-methylenedioxy-phenoxy)methyl-piperidine C.H.NC1.HCl and has the chemical name (1S-cis)-4-(3, hydrochloride. Paroxetine hydrochloride melts at 120-138 4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphtha C., has a molecular weight of 374.8 g/mol, and has a lenamine hydrochloride. The preparation of Sertraline may solubility of 5.4 mg/mL in water. The structure of paroxetine be carried using preparatory methods Such as those hydrochloride is presented below. described in Welch, et al. European Patent Application US 2005/0176680 A1 Aug. 11, 2005

30,081 and U.S. Pat. No. 4,536,518. The chemical structure age, body weight, and response of the individual patient. In of Sertraline hydrochloride is presented below. general, the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 300 mg. Preferably, a daily dose range should be between about 10 NH OCI mg to about 200 mg. Most preferably, a daily dose range should be between about 25 mg to about 100 mg. In certain embodiments, a daily dosage of 40, 60, or 80 mg may be preferred depending upon patient response. In managing the patient, the therapy may be initiated at a lower dose, perhaps about 5 mg to about 10 mg and increased up to about 20 mg or higher depending-on the patient's global response. It may be necessary to use dosages outside these ranges in Some CSCS.

Cl 0.095) Femoxetine

C 0096. Femoxetine is an antidepressant reported in U.S. Pat. No. 3,912,743. The chemical name for femoxetine is (3R-trans)-3-4-Methoxyphenoxy)-methyl-1-methyl-4- 0.091 The size of a prophylactic or therapeutic dose of phenylpiperidine. In certain instances, femoxetine may be Sertraline in the acute or chronic management of disease will administered in the form of a hydrochloride salt. The dose, vary with the severity of the condition to be treated and the and perhaps the dose frequency, will also vary according to route of administration. The dose, and perhaps the dose the age, body weight, and response of the individual patient. frequency, will also vary according to the age, body weight, In general, the total daily dose ranges, for the conditions and response of the individual patient. In general, the total described herein, is from about 1 mg to about 900 mg. daily dose ranges, for the conditions described herein, is Preferably, a daily dose range should be between about 10 from about 1 mg to about 500 mg. Preferably, a daily dose mg to about 200 mg. The chemical structure of femoxetine range should be between about 10 mg to about 200 mg. Most is presented below. preferably, a daily dose range should be between about 20 mg to about 100 mg. In certain embodiments, a daily dosage of 30, 50, 70, or 80 mg may be preferred depending upon patient response. In managing the patient, the therapy may be initiated at a lower dose, perhaps about 10 mg to about 15 mg and increased up to about 20 mg or higher depending on the patient's global response. It may be necessary to use dosages outside these ranges in Some cases. Additional information for Sertraline hydrochloride including product information, dosage amounts, and administration is given in Physicians' Desk Reference, 48th Edition, 1994, pp. 2000 2003. O097 Indalpine (UPSTENE(R) 0092 Clomipramine 0098 Indalpine is serotonin reuptake inhibitor that may 0.093 Clomipramine is an antidepressent described in be used to treat depression. Indalpine was disclosed in U.S. U.S. Pat. No. 3,467,650. In certain instances, clomipramine Pat. No. 4,064.255. The pharmacological activity is dis may be administered in the form of a hydrochloride salt cussed in G. LeFur et al. Life Sci. 1978, 23, 1959 and R. named Anafranil. Clomipramine has the chemical name Ashkenazi et al. Brit. J. Pharmacol. 1983, 79, 765 and 915. 3-Chloro-10,11-dihydro-N,N-dimethyl-5H-dibenzb,f In certain instances, indalpine can be administered as the aZepine-5-propanamine. The Structure of clominpramine is monohydrochloride Salt. Indalpine has the chemical name presented below. 3-2-(4-Piperidinyl)ethyl)-1H-indole and has the structure presented below.

Cl N N1

0094. The size of a prophylactic or therapeutic dose of clominpramine in the acute or chronic management of disease will vary with the severity of the condition to be NH treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the US 2005/0176680 A1 Aug. 11, 2005

0099. The dose, and perhaps the dose frequency, will also receptor had been termed 5-HT before researchers deter vary according to the age, body weight, and response of the mined that it is structurally very similar to the 5-HT individual patient. In general, the total daily dose ranges, for receptors. The 5-HT2A, 5-HT, and 5-HT, receptors are the conditions described herein, is from about 1 mg to about single protein molecules of 458-471 amino acids. Each of 900 mg. Preferably, a daily dose range should be between the receptors are thought to be linked to the phosphoinositol about 10 mg to about 200 mg. hydrolysis Signal transduction System via the a Subunit of the 0100 Alaproclate Gq GTP binding protein. 0110. The 5-HT, receptor is located in the cortex, claus 0101 Alaproclate is a serotonin reuptake inhibitor that trum and basal ganglia. Biological testing in rodents has the chemical name 2-(4-chlorophenyl)-1,1-dimethyl revealed that Stimulation or agonism of 5-HT2A receptors 2-aminopropanoate. In certain instances, Alaproclate is causes head Shaking and may mediate the effects of hallu administered as a hydrochloride Salt. The size of a prophy cinogens. 5-HT2A modulators include compounds that are lactic or therapeutic dose in the acute or chronic manage 5-HT, receptor antagonists, which block the activity of ment of disease will vary with the severity of the condition agonists and have little to no intrinsic activity on the to be treated and the route of administration. The dose, and receptor, and 5-HT, inverse agonists, which are com perhaps the dose frequency, will also vary according to the pounds that have negative intrinsic activity on the receptor. age, body weight, and response of the individual patient. In 5-HT2A receptor antagonists, e.g., ritanserin, have been general, the total daily dose ranges, for the conditions reported to improve Sleep quality. 5-HT2A receptor antago described herein, is from about 1 mg to about 900 mg. nists are also useful in treating migraine, depression, and Preferably, a daily dose range should be between about 10 Schizophrenia. mg to about 200 mg. 0111. MDL 100,907 0102) Cericlamine 0112 MDL 100,907 is a potent 5-HT, receptor antago 0103) Cericlamine has the chemical name (+)3-(3,4- nist and thus is useful for treating a variety of conditions. For dichlorophenyl)-2-dimethylamino-2-methylpropan-1-ol. example, MDL 100,907 has been evaluated for the treatment The preparation of cericlamine is described in EP 237 366, of various neurological disorders, including Schizophrenia. J. Chem. Soc. Perkin Trans. I 1996, 1495-1498, and U.S. WO 99/56750 and J. Pharm. Exp. Ther: 1996, 277, 968 Pat. No. 6,121,491. The dose, and perhaps the dose fre 9881. MDL 100,907 has been shown to exert a tonic quency, will also vary according to the age, body weight, inhibitory influence on dopamine efflux in the medial pre and response of the individual patient. In general, the total frontal cortex. See European Journal of Pharmacology daily dose ranges, for the conditions described herein, is 1995, 273,273-279. MDL 100,907 is highly selective in its from about 1 mg to about 900 mg. Preferably, a daily dose activity at the 5-HT, receptor compared to other receptors, range should be between about 10 mg to about 200 mg. and, as Such, has reportedly fewer Side effects. It has been Ifoxetine shown to have a better CNS safety index relative to the 01.04] reference compounds haloperiodol, clozapine, risperiodone, 0105 Ifoxetine has the chemical name (+)-bis-cis-3- ritanserin, and amperozide in preclinical testing. JPET 1996, hydroxy-4-(2,3-dimethyl-phenoxy)-piperidine sulfate. The 277, 968-981. In addition, MDL 100,907 is useful in the dose, and perhaps the dose frequency, will also vary accord treatment of Sleep disorders, Such as insomnia and obstruc ing to the age, body weight, and response of the individual tive sleep apnea. See U.S. Pat. Nos. 6,277,864 and 6,613, patient. In general, the total daily dose ranges, for the 779. conditions described herein, is from about 1 mg to about 900 mg. Preferably, a daily dose range should be between about 0113. MDL 100.907 has the chemical name (+)-O-(2,3- 10 mg to about 200 mg. dimethoxyphenyl)-1-2-(4-fluorophenyl)ethyl-4-piperidine methanol and can be prepared as described in U.S. Pat. No. 0106 Additional serotonin reuptake inhibitors contem 5,134,149 and WO 91/18602. Compounds that are structur plated for the instant invention include buspirone, cloVOX ally similar to MDL 100,907 are described in EP 0208235. amine, cyanodothiepin, dapoxetine, imipramine, litoxetine, In addition, the present invention encompasses a composi lofepramine, nefazodone, norZimeldine, traZodone, Ven tion comprising mixture of MDL 100,907 and its enanti lafaxine, Vicqualine, and Zimeldine. omer. The structure of MDL 100,907 is presented below: 0107 5-HT Modulators 0108 Originally, four main subgroups of 5-HT receptors, OH 1. named 5-HT, 5-HT, 5-HT, and 5-HT, were recognized based on receptor binding profiles, the biological activity of the ligands for the receptors, and Secondary messenger coupling. Additional research has lead to the identification of 5-HT, 5-HT, 5-HT, and 5-HT7 receptors. The recog nition that different subtypes of 5-HT exist is important for drug design because compounds which Selectivity inhibit only one of the 5-HTSubtypes may offer reduced side effects compared to a therapeutic agent that broadly inhibits many of the 5-HT Subtypes. 0114. The dosage range at which MDL 100,907 exhibits 0109) The 5-HT, receptor family is comprised of the its ability to block the effects of serotonin at the 5-HT2A 5-HT2A, 5-HT, and 5-HT, receptor subtypes. The 5-HT receptor can vary depending upon the particular disease or US 2005/0176680 A1 Aug. 11, 2005 condition being treated and its Severity, the patient, the 759-768). In rodents, it has been shown that this compound formulation, other underlying disease States that the patient predominantly binds to the regions of the brain containing is Suffering from, and other medications that may be con the 5-HT, receptor (M. Rinaldi-Carmona et al. Life Sciences currently administered to the patient. Generally, MDL 100, 1993, 54, 119-127). SR 46349B has the chemical name 907 will exhibit its serotonin 5-HT, antagonist properties at (1Z.2E)-1-(2-fluorophenyl)-3-(4-hydroxyphenyl)prop-2-en dosages of between about 0.001 mg/kg of patient body 1-one-O-(2-dimethyl-aminoethyl)oxime hemifumarate. SR weight/day to about 100 mg/kg of patient body weight/day. 46349B can be prepared as described in EP 0373998 B1. Sustained release formulations may contain multiples of the The dose, and perhaps the dose frequency, will also vary foregoing dosages depending upon over what period the according to the age, body weight, and response of the active ingredient is released. The dosage of the compounds individual patient. In general, the total daily dose ranges, for of the present invention may be determined by administering the conditions described herein, is from about 1 mg to about the compound to an animal and determining the plasma level 900 mg. Preferably, a daily dose range should be between of the active ingredient. about 10 mg to about 200 mg. The structure of SR 46349B is presented below: 0115. In certain instances, it is advantageous to admin ister MDL 100,907 in the form of a prodrug. A prodrug is a compound that gets converted to the active drug after the compound is administered. Carr and coworkers have described ester derivatives of MDL 100,907 that function as prodrugs for MDL 100,907. See U.S. Pat. Nos. 6,028,083 and 6,063,793. The structure of the ester derivatives of MDL C-O- 100,907, as will be referred to as “Pro MDL 100,907.” -N-1-N hereafter, is presented below: 0119) YM 992 0120 YM 992 is an morpholine derivative described in by Takeuchi and coworkers in Eur: J. Pharmacol. 1997, 329, 27-35. The chemical name of YM 992 is (S)-2-(7-Fluoro 2,3-dihydro-1H-inden-4-yl)-oxymethylmorpholine hydro chloride. In general, the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 900 mg. Preferably, a daily dose range should be between about 10 mg to about 200 mg. The structure of YM 992 is presented below:

0116 wherein, R is C-C alkyl. Pro MDL 100,907 also HoHCI refers to a Stereoisomer or pharmaceutically acceptable Salt thereof. Procedures for the preparation of Pro MDL 100,907 can be found in U.S. Pat. Nos. 6,028,083 and 6,063,793. The dosage range at which Pro MDL 100,907 exhibits its ability to block the effects of Serotonin at the 5-HT2A receptor can vary depending upon the particular disease or condition being treated and its Severity, the patient, the formulation, C other underlying disease States that the patient is Suffering from, and other medications that may be concurrently administered to the patient. Generally, Pro MDL 100,907 0121 Fananserin will exhibit its serotonin 5-HT modulator properties at 0.122 Fananserin is a 5-HT2A receptor antagonist dosages of between about 0.001 mg/kg of patient body described by Doble A. and coworkers in Br. J. Pharmacol. weight/day to about 100 mg/kg of patient body weight/day. 1992, 105, 27-36. In general, the total daily dose ranges, for Sustained release formulations may contain multiples of the the conditions described herein, is from about 1 mg to about foregoing dosages depending upon over what period the 900 mg. Preferably, a daily dose range should be between active ingredient is released. The dosage of the compounds about 10 mg to about 200 mg. The structure of fananserin is of the present invention may be determined by administering presented below: the compound to an animal and determining the plasma level of the active ingredient. O / \ 0117 SR 46349B N F F 0118 SR 46349B is a highly selective antagonist of the OFS N N / 5-HT, receptor. SR 46349B has virtually no affinity for the 5-HT1A, 5-HT, and 5-HT, receptors, and has a moderate affinity for the 5-HT, receptor. In studies on isolated tissues, the absence of activity of SR 46349B on rat stomach fundus indicates a 5-HT2A specificity versus 5-HT (M. Rinaldi-Carmona et al. J. Pharmacol. Exp. Ther: 1992, US 2005/0176680 A1 Aug. 11, 2005

0123 Oxazolidine Compounds A 0.124. A series of oxazolidine derivatives that have 5-HT, receptor-antagonizing properties are described in WO 98/38189. Methods for preparing the oxazolidine com pounds are given in WO 98/38189. In general, the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 900 mg. Preferably, a daily dose range should be between about 10 mg to about 200 mg. The generic Structure of the Oxazolidine Compounds A, as disclosed in WO 98/38189, is presented below. The defini tions of the Substituents of the generic Structure can be found in WO 98/38189 which is hereby incorporated by reference. 0129. In certain embodiments, the piperidinyl compound A is N-1-2-(1,3-Dioxolan-2-yl)ethylpiperidin-4-yl)-N- (4-fluorobenzyl)-N'-(4-isobutoxybenzyl)carbamide, hydro chloride; N-1-2-(1,3-Dioxan-2-yl)ethylpiperidin-4-yl)- N-(4-fluorobenzyl)-2-4-(2-hydroxy-2- methylpropoxy)phenyl)acetamide, tartrate, N-(4- Fluorobenzyl)-N-(piperidin-4-yl)-2-(4- isobutoxyphenyl)acetamide; N-(1-3-(3.5- Dimethylpiperidin-1-yl)propylpiperidin-4-yl)-N-(4- 0125 Phenylindole Compounds. A fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide, dihydrochloride; 1-3-(4-(4-Fluorobenzyl)-2-(4-isobutox 0126. A series of phenylindole compounds that are modu yphenyl)acetylamino)piperidin-1-yl)propylpiperidin-4- lators of the human 5-HT, receptor have been described by carboxylic acid methyl ester, dihydrochloride; N-(4-Fluo Castro Pineiro and coworkers in U.S. Pat. No. 6,486,153. robenzyl)-2-(4-isobutoxyphenyl)-N-1-2-(1- Methods for preparing the phenylindole compounds are methylpyrrolidin-2-yl)ethylpiperidin-4-yl)acetamide, presented in U.S. Pat. No. 6,486,153. n general, the total dioxalate; N-(1-3-(2,6-Dimethylmorpholin-4-yl)propylpi daily dose ranges, for the conditions described herein, is peridin-4-yl)-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)ac from about 1 mg to about 900 mg. Preferably, a daily dose etamide, dioxalate; N-(4-Fluorobenzyl)-N-(1-3-(3-hydrox range should be between about 10 mg to about 200 mg. The ypiperidin-1-yl)propylpiperidin-4-yl)-2-(4- generic Structure of the Phenylindole Compounds A, as isobutoxyphenyl)acetamide, dioxalate; N-(4-Fluorobenzyl)- disclosed in U.S. Pat. No. 6,486,153, is presented below. The 2-(4-isobutoxyphenyl)-N-(1-3-(2-methylpiperidin-1- definitions of the Substituents of the generic structure can be yl)propylpiperidin-4-yl)acetamide, dioxalate; N-(4- found in U.S. Pat. No. 6,486,153 which is hereby incorpo Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-1-(3-pyrrolidin-1- rated by reference. yl-propyl)piperidin-4-yl)acetamide, dioxalate; N-(1-3-(2, 5-Dimethylpyrrolidin-1-yl)propylpiperidin-4-yl)-N-(4- fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide, dioxalate; N-(4-Fluorobenzyl)-N-(1-3-(3-hydroxymethylpiperidin-1- yl)propylpiperidin-4-yl)-2-(4-isobutoxyphenyl)acetamide, dioxalate; N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N- {1-3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)propylpip eridin-4-yl)acetamide, oxalate; N-2-(4-Fluorophenyl )ethyl-2-(4-isobutoxyphenyl)-N-(1-3-(4-(S)-isopropyl-2- OXO-Oxazolidin-3-yl)propylpiperidin-4-yl)acetamide, oxalate; N-2-(4-Fluorophenyl)ethyl-N-(1-3-(4-(S)-iso propyl-2-oxo-oxazolidin-3-yl)propylpiperidin-4-yl)-2-(4- propoxyphenyl)acetamide, oxalate, N-(4-Fluorobenzyl)-N- 0127 Piperidinyl Compounds B {1-3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)propyl) 0128. A series of piperidinyl compounds that modulate piperidin-4-yl)-2-(4-propoxyphenyl)acetamide, Oxalate; the 5-HT, receptor have been described in U.S. patent N-1-2-(1,3-Dioxan-2-yl)ethylpiperidin-4-yl)-N-(4-fluo application 2004/0106600. Methods for preparing the pip robenzyl)-2-(4-isobutoxyphenyl)acetamide, oxalate; N-1- eridinyl compounds are presented in U.S. patent application 2-(1,3-Dioxan-2-yl)ethylpiperidin-4-yl)-N-2-(4-fluo 2004/0106600. In general, the total daily dose ranges, for the rophenyl)ethyl]-4-isobutoxyphenyl)acetamide, Oxalate; conditions described herein, is from about 1 mg to about 900 N-1-2-(1,3-Dioxan-2-yl)ethylpiperidin-4-yl)-N-2-(4- mg. Preferably, a daily dose range should be between about fluorophenyl)ethyl-2-(4-propoxyphenyl)acetamide, 10 mg to about 200 mg. The generic structure of the oxalate; N-1-2-(1,3-Dioxan-2-yl)ethylpiperidin-4-yl)-N- piperidinyl compounds A, as disclosed in U.S. patent appli (4-fluorobenzyl)-2-(4-propoxyphenyl)acetamide, tartrate; cation 2004/0106600, is presented below. The definitions of N-1-2-(1,3-Dioxan-2-yl)ethylpiperidin-4-yl)-N-(4-fluo the Substituents of the generic Structure can be found in U.S. robenzyl)-N-(4-isobutoxybenzyl)carbamide, tartrate; N-1- patent application 2004/0106600 which is hereby incorpo 2-(1,3-Dioxan-2-yl)ethylpiperidin-4-yl)-N-(4-fluoroben rated by reference. Zyl)-2-(4-fluorophenyl)acetamide, tartrate; N-1-2-(1,3-

US 2005/0176680 A1 Aug. 11, 2005 weight per day. Unless otherwise Stated all weights of active Clin. Pharmacol. 1970, 3, 12-17). The synthesis and bio ingredients are calculated in terms of drug per se. The logical activity of lofepramine was described in British Pat. desired dose is preferably presented as two, three, four, five No. 1,177.525. A preferred method for preparing or more Sub-doses administered at appropriate intervals lofepramine has been reported by E. Eriksoo and O. Rohte throughout the day. These Sub-doses may be administered in in Arzneimittelforschung 1970, 20, 1561-1569. However, unit dosage forms, for example, containing 5 to 50 mg. this known method presents difficulties of a pronounced 0.141. Desipramine nature, especially when used in full-scale production. Thus, Slight unintentional variations in the process conditions 0142. Desipramine has the chemical name 10,11-Dihy often result in discoloured products, which are very difficult dro-N-methyl-5H-dibenzb.fazepine-5-propanamine and is to purify. An improved procedure for the preparation of described in U.S. Pat. No. 3,454,554. The pharmacology is lofepramine is described in U.S. Pat. No. 4,172,074. Addi described by P. D. Hrdina et al. in Prog. Neuropsychophar tional reports on the biological activity of lofepramine can macol. 1980, 4, 591. Desipramine is generally administered be found in G. Plym Forshell et al. Eur: J. Clin. Pharmacol. as a hydrochloride Salt marketed under the name Norpramin. Desipramine hydrochloride occurs as crystals which are 1976, 9, 291 and S. Wright et al. Arzneimittel-Forsch 1976, Soluble in water. The dose, and perhaps the dose frequency, 26, 1167. Lofepramine has the chemical name 4'-chloro-2- will also vary according to the age, body weight, and {3-(10,11-dihydro-5H-dibenz(b,f)-azepinyl-(5)-propyl response of the individual patient. In general, the total daily methylamino-acetophenone and the structure is presented dose ranges, for the conditions described herein, is from below. about 1 mg to about 900 mg. Preferably, a daily dose range should be between about 10 mg to about 200 mg. The Structure of desipramine is presented below. Cs-O -- OJO N

N--N H 0147 The size of a prophylactic or therapeutic dose of lofepramine in the acute or chronic management of disease 0143 Maprotiline will vary with the severity of the condition to be treated and the route of administration. The dose, and perhaps the dose 0144. Maprotiline has the chemical name N-Methyl-9, frequency, will also vary according to the age, body weight, 10-ethanoanthracene-9(10H)-propanamine and is described and response of the individual patient. In general, the total in U.S. Pat. No. 3,399.201. The pharmacology is described daily dose ranges, for the conditions described herein, is by R. M. Pinder et al. in Drugs 1977, 13, 321. Maprotiline from about 1 mg to about 300 mg. Preferably, a daily dose is generally administered as a hydrochloride Salt marketed range should be between about 10 mg to about 200 mg. Most under the name Ludiomil. Maprotiline hydrochloride occurs preferably, a daily dose range should be between about 30 as crystals which are slightly Soluble in water. The dose, and mg to about 120 mg. In certain embodiments, a daily dosage perhaps the dose frequency, will also vary according to the of 50, 75, or 100 mg may be preferred depending upon age, body weight, and response of the individual patient. In patient response. In managing the patient, the therapy may general, the total daily dose ranges, for the conditions be initiated at a lower dose, perhaps about 5 mg to about 10 described herein, is from about 1 mg to about 900 mg. mg and increased up to about 20 mg or higher depending-on Preferably, a daily dose range should be between about 10 the patient's global response. It may be necessary to use mg to about 200 mg. The Structure of maprotiline is pre dosages outside these ranges in Some cases. sented below. 0148 Reboxetine 0149 Reboxetine is active on the central nervous system and has been used to treat depression, oppositional defiant disorder, attention-deficit/hyperactivity disorder, and con duct disorder. See WO 99/15163, WO95/15176, and WO 99/15177. Reboxetine does not act like most antidepres sants. Reboxetine is ineffective in the 8-OH-DPAT hypoth O ermia test, indicating that reboxetine is not a SSRI. Brian E. Leonard, “Noradrenaline in basic models of depression .'European-Neuropsychopharmacol., 7 Suppl. 1 pp. S 11-6 0145 Lofepramine and S71-3 (April 1997). Reboxetine is a norepinephrine reuptake inhibitor, with only marginal Serotonin and no 0146 Lofepramine has been found clinically effective dopamine reuptake inhibitory activity. Reboxetine displayS against disorders related to the central nervous System, no anticholinergic binding activity in different animal mod especially mental depressions (B. Siwers et al., Europ. J. els, and is Substantially devoid of monoamine oxidase US 2005/0176680 A1 Aug. 11, 2005

(MAO) inhibitory activity. Racemic reboxetine exhibits a The reduction in dosage does not lead to a reduction in pharmacological Selectivity of Serotonin (K)/norepineph efficacy, but the reduction or elimination of various adverse rine (K) of about 80. side effects was observed. 0150 Reboxetine is a safe drug, and its use in ADHD, in 0154) In particular, because an optically pure (S,S) rebox both adults and children, is a Superior treatment for that etine Selectively inhibits norepinephrine reuptake compared disorder because of its improved Safety. The compound is to Serotonin reuptake, adverse Side effects associated with particularly Selective, having few if any physiological Serotonin reuptake are reduced or eliminated. Such adverse effects besides those on norepinephrine processing, and Side effects include, but are not limited to, gastrointestinal therefore is free of side effects and unwanted activities. disturbances, anxiety, Sexual dysfunction, and undesirable Further, it is effective at relatively low doses, as discussed Side effects associated with drug-drug interactions. below, and may safely and effectively be administered once per day. Thus, difficulties created by the multiple dosing of 0155 Oxaprotiline patients, who are children and disorganized adults, are 0156 Oxaprotiline has the chemical name (+)-O-(Me completely avoided. thylamino)-methyl-9,10-ethanoanthracene-9(10H)-ethanol. (CAS registry number: 56433-44-4). Oxaprotiline is a pro 0151. The racemate form of reboxetine is well tolerated mosing therapeutic agent for the treatment of depression. In and has a wide Safety range. The effective dose of reboxetine an experiment where 24 patients (37 trials) with major for ADHD is in the range from about 1 mg/day to about 100 depression where treated with Oxaprotiline over 3 weeks, mg/day. The preferred adult dose is in the range from about the-patients had a significant reduction in their Hamilton 5 to about 80 mg/day, and a more highly preferred adult dose Scores. The dose, and perhaps the dose frequency, will also is from about 10 to about 60 mg/day. The children's dose of vary according to the age, body weight, and response of the course is Smaller, in the range from about 1 to about 70 mg/day, more preferably from about 5 to about 60 mg/day individual patient. In general, the total daily dose ranges, for and still more preferably from about 4 to about 10 mg/day. the conditions described herein, is from about 1 mg to about The optimum dose for each patient, as always, must be Set 900 mg. Preferably, a daily dose range should be between by the physician in charge of the case, taking into account about 10 mg to about 200 mg. the patient's size, other medications which the patient O157 Fezolamine requires, Severity of the disorder and all of the other cir 0158 Fezolamine has the chemical name N,N-dimethyl cumstances of the patient. 3,4-diphenyl-1H-pyrazole-1-propanamine-(E)-2-butenedio 0152 Reboxetine was first taught by U.S. Pat. No. 4,229, ate (CAS registry number: 80410-36-2) and shows antide 449 and has the chemical name 2-O-(2-ethoxy)phenoxy preSSant activity. The therapeutic affect of feZolamine is benzylmorpholine. Reboxetine is also described in U.S. Pat. attributed to its ability to inhibit norepinephrine reuptake. In Nos. 5,068,433; 5,391,735; 6,642,235; and in GB 2,167,407. fact, feZolamine was 3 to 4 fold more Selective in blocking Individual stereoisomers of reboxetine can be obtained by SynaptoSomal uptake of norepinephrine compared to Sero resolution of the racemic mixture of enantiomers using tonin or dopamine in in vitro assayS. See E. R. Baizman et conventional methods generally known by those skilled in al. J. Pharmacol. Exp. Ther. 1987 243, 40-54. Fezolamine the art. Such methods include, but are not limited to, also prevented the depressant effects of reserpine and tetra resolution by Simple crystallization and chromatographic benzine in behavioral tests conducted on monamine depleted techniques, for example, as set forth in GB 2,167,407. The animals. The dose, and perhaps the dose frequency, will also Structure of reboxetine is presented below. vary according to the age, body weight, and response of the individual patient. In general, the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 900 mg. Preferably, a daily dose range should be between On 1 about 10 mg to about 200 mg. 0159 Tomoxetine 0160 Tomoxetine is a notably safe drug for use in adults and children for treatment of attention deficit hyperactivity NH disorder. It is a Superior treatment for that disorder because of its improved safety. Tomoxetine is effective at relatively su low doses and may safely and effectively be administered once per day. In addition, the results from animal Studies 0153 Generally, reboxetine is administered as the race indicate that tomoxetine Selectively inhibits norepinephrine mate. However, in certain instances, it may be advantageous uptake indicating that tomoxetine would be useful in treating to administer reboxetine in the form of a single enantiomer. depression. Tomoxetine has been administered in Single oral Specifically, it has been found that compositions containing doses up to 90 mg to humans. In addition, no Serious an optically pure (S,S) reboxetine are about 5 to about 8.5 drug-related adverse effects were observed when tomoxetine times more effective at inhibiting the reuptake of norepi was administered to humans at a dosage of 20 or 40 mgb.i.d. nephrine than compositions containing the racemic mixture for 7 days. of the (R,R) and (S,S) Stereoisomers. Accordingly, the 0161 Tomoxetine has the chemical name (R)-(-)-N- typical daily dosage of the racemic mixture (i.e., commer methyl-3-(2-methylphenoxy)-3-phenylpropylamine. The cially available reboxetine) can be reduced by about 50% to mechanism of tomoxetine's activity is attributed to its ability about 80% when using an optically pure (S,S) reboxetine. to inhibit norepinephrine reuptake. See Gehlert, et al. Neu US 2005/0176680 A1 Aug. 11, 2005

roscience Letters 1993, 157, 203-06. Tomoxetine is quite invention. Dopamine reuptake inhibitors can be identified active in that function, and moreover is Substantially free of using the rat corpus striatum assay described in U.S. patent other central nervous System activities at the concentrations application 20040180857, which is hereby incorporated by or doses at which it effectively inhibits norepinephrine reference. In general, a dose of a dopamine reuptake inhibi reuptake. Thus, it is quite free of Side effects and is properly tor or a pharmaceutically acceptable Salt thereof Suitable for considered to be a Selective drug. Tomoxetine is usually administration to a human will be in the range of 0.01 to 50 administered as the hydrochloride Salt. mg per kilogram body weight of the recipient per day, 0162 The effective dose of tomoxetine for ADHD is in preferably in the range of 0.1 to 3 mg per kilogram body the range from about 5 mg/day to about 100 mg/day. The weight per day. Unless otherwise Stated all weights of active preferred adult dose is in the range from about 10 to about ingredients are calculated in terms of drug perse. In certain 80 mg/day, and a more highly preferred adult dose is from embodiments, the desired dose is presented as two, three, about 20 to about 60 mg/day. The children's dose of course four, five or more Sub-doses administered at appropriate is Smaller, in the range from about 5 to about 70 mg/day, intervals throughout the day. These Sub-doses may be more preferably from about 10 to about 60 mg/day and still administered in unit dosage forms, for example, containing more preferably from about 10 to about 50 mg/day. The about 5 to 50 mg. optimum dose for each patient, as always, must be set by the physician in charge of the case, taking into account the 0169 Amineptine patient's Size, other medications which the patient requires, severity of the disorder and all of the other circumstances of 0170 Amineptine is a synthetic, atypical tricyclic anti the patient. depressant with central nervous System Stimulating effects. It has the chemical name of 7-(10,11-dihydro-5H-dibenzo 0163 Since tomoxetine is readily orally absorbed and a.d-cycloheptene-5-yl)aminoheptanoic acid and is avail requires only once/day administration, there is little or no reason to administer it in any other way than orally. It may able as either the free base (CAS registry number 575746 be produced in the form of a clean, Stable crystal, and thus 09-1; shown below) or the hydrochloride salt (CAS registry is easily formulated in the usual oral pharmaceutical forms, number 302724-08-3). It is also known as S-1694, Maneon Such as tablets, capsules, Suspensions, and the like. The and Survector. Preparation of amineptine is described in usual methods of pharmaceutical Scientists are applicable. It U.S. Pat. No. 3,758,528 and No. 3,821,249. may usefully be administered, if there is any reason to do So in a particular circumstance, in other pharmaceutical forms, Such as injectable Solutions, depot injections, Suppositories and the like, which are well known to and understood by pharmaceutical Scientists. It will Substantially always be preferred, however, to administer tomoxetine as a tablet or CuO capsule and Such pharmaceutical forms are recommended. HO O HN 0164 (S,S)-Hydroxybupropion 0165 (S,S)-hydroxybupropion is a metabolite of bupro pion that Selectively inhibits norepinephrine reuptake and does not significantly inhibit dopamine reuptake. Methods for the preparation of (S,S)-hydroxybupropion are described in U.S. Pat. No. 6,342,496. (S,S)-hydroxybupropion has the 0171 Amineptine is an indirect dopamine agonist, Selec chemical name (S,S)-2-(3-chlorophenyl)-2-hydroxy-3.5.5- tively inhibiting dopamine uptake and inducing dopamine trimethyl-moipholinol and the Structure is given below. release, with additional Stimulation of the adrenergic System. Its antidepressant effects are similar to other tricyclic anti depressant drugs but it has a more rapid action, is better tolerated and has little cardiovascular, analgesic or anorectic effects. It produces a similar Spectrum of pharmacological effects to psychomotor stimulants in Schedule II of the 1971 Convention on Psychotropic Substances. Recently, the use of amineptine in the treatment of depression has been described by S. M. Channabasavanna et al. in Indian Journal of Psychiatry 1997, 39, 147-53. C 0172 Bupropion 0166 The present invention contemplates the use of 0173 Bupropion is marketed under the tradename norepinephrine reuptake inhibitors in general, including WELLBUTRINGR) by GlaxoSmithKline for the treatment of nortriptyline, maprotiline, protriptyline, trimipramine, Ven depression. In certain instances, bupropion is administered lafaxine, amitriptyline, amoxapine, doxepin, nefazodone, as its hydrochloride salt. WELLBUTRINGR (bupropion and lamotrigine. hydrochloride), is an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, Selec 0167 Dopamine Reuptake Inhibitors tive Serotonin re-uptake inhibitor, or other known antide 0168 A large number of dopamine reuptake inhibitors preSSant agents. Its structure closely resembles that of dieth are known in the art and are amenable to the present ylpropion; it is related to phenylethylamines. It has the US 2005/0176680 A1 Aug. 11, 2005 22 chemical names 1-(3-chlorophenyl)-2-1,1-dimethylethy Science 1999, 19, 4169-4179. Its chemical name is 1-2- l)amino-1-propanone; (+)-2-(tert-butylamino)-3'-chloro (diphenylmethoxy)ethyl-4-(3-phenylpropyl)piperazine propiophenone; m-chloro-O-(tert-butylamino)propiophe dihydrochloride. none; and amfebutamon(e). Its preparation is described in U.S. Pat. No. 3,819,706 and No. 3,885,046. 1. N l Cho 0.174 Bupropion is a novel, non-tricyclic antidepressant with a primary pharmacological action of monoamine uptake inhibition. The drug resembles a psychoStimulant in 0180 GBR-12935 inhibits the dopamine and norepineph terms of its neurochemical and behavioural profiles in Vivo, rine transporters with KS of 21.5 nM and 225 nM, respec but it does not reliably produce stimulant-like effects in tively. It does not inhibit the serotonin transporter (K=6.5 humans at clinically prescribed doses. Bupropion binds with AlM). It acts by binding to a nondopaminergic piperazine site modest Selectivity to the dopamine transporter, but its in blood platelets and brain that has been identified as behavioural effects have often been attributed to its inhibi cytochrome P450. tion of norepinephrine uptake. 0181 Venlafaxine (EFFEXOR(R) 0.175. The neurochemical mechanism of the antidepres Sant effect of bupropion is not known. Bupropion is a 0182 Venlafaxine is dopamine reuptake inhibitor. Its relatively weak inhibitor of the neuronal uptake of norepi hydrochloride Salt is marketed under the tradename nephrine, Serotonin, and dopamine, and does not inhibit EFFEXOR(R) and used in the treatment of bipolar disorder. monoamine oxidase. Bupropion produces dose-related cen It has the chemical names (t)-1-2-(dimethylamino)-1-(4- tral nervous system (CNS) stimulant effects in animals, as methyoxyphenyl)ethylcyclohexanol; N,N-dimethyl-2-(1- evidenced by increased locomotor activity, increased rates hydroxycyclohexyl)-2-(4-methoxyphenyl)ethylaminel and of responding in various Schedule-controlled operant behav venlafexine. Its prepration is described in U.S. Pat. No. ior tasks, and, at high doses, induction of mild Stereotyped 4,535,186. A review of its pharmacology and clinical effi behavior. cacy can be found in the Journal of Clinical Psychiatry 0176). In humans, following oral administration, peak (Montgomery, S. A. J. Clin. Psychiatry 1993, 54, 119-126.) plasma bupropion concentrations are usually achieved 5 within 2 hours, followed by a biphasic decline. The terminal phase has a mean half-life of 14 hours, with a range of 8 to OH 24 hours. The distribution phase has a mean half-life of 3 to 4 hours. The mean elimination half-life (tSD) of bupropion after chronic dosing is 21 (+9) hours, and steady-state plasma concentrations of bupropion are reached within 8 days. Plasma bupropion concentrations are dose-propor tional following single doses of 100 to 250 mg. Bupropion inhibits the dopamine and norepinephrine transporters with Ks of 2.8 uM and 1.4 uM, respectively. It does not inhibit the serotonin transporter (K=45 uM). OMe 0177. A recent experiment examined monoaminergic involvement in the discriminative stimulus effects of bupro 0183 Venlafaxine is a representative of a new class of pion (Katz, T. P. Psychopharmacology (Berl) 1997, 134(2), antidepressants (SNRIs) which inhibit selectively the uptake 201-12). Rats were trained to press one lever when injected i.p. with bupropion (17.0 mg/kg), and another lever when of Serotonin and noradrenaline, but-in contrast to tricy injected with Saline. The results demonstrate Strong Simi clicS-show no affinity for neurotransmitter receptors. larities with those obtained using other dopamine uptake 0184] 2 B-Propanoyl-3|3-(4-tolyl)-tropane (PTT) inhibitors as training drugs, and Support the View that the behavioural effects of bupropion are primarily mediated by 0185. 2B-propanoyl-3,3-(4-tolyl)-tropane or 3.3-(4-(1-me dopaminergic mechanisms. thylphenyl)-8-azabicyclo3.2.1]octane are also known as PTT. PTT binds with high affinity to the dopamine trans 0178 GBR-12935 porter (ICso-8.2+1.6) and with lower afinity for the seroto 0179 GBR-12935 is a dopamine reuptake inhibitor nin (K=130=10) and norepinephrine transporters described by A. R. Burkeyl and coworkers in J. of Neuro (K=160+1.6). US 2005/0176680 A1 Aug. 11, 2005 23

active ingredients are calculated in terms of drug per se. In certain embodiments, the desired dose is presented as two, Me three, four, five or more Sub-doses administered at appro OEt priate intervals throughout the day. These Sub-doses may be administered in unit dosage forms, for example, containing about 5 to 50 mg. 0192 GABA Binding Assay 0193 The affinity of a compound to bind to a GABA receptor can be measured using procedures known in the art. 0186 The preparation of PTT can be found in U.S. Pat. In addition, assay kits for determining GABA-receptor bind No. 5,763,455. The dopamine reuptake inhibitory properties ing affinity can be purchased from MDS Pharma Services. of 2B-propanoyl-3B-(4-tolyl)-tropane have been described For representative examples of procedures to determine by J. A. Lile and coworkers in J. Pharmacol. Exp. Ther. GABA-receptor binding affinity see Enna, S.J.; Snyder, S. 2002, 303, 640-8. H. Mol. Pharmacol. 1976, 13, 442; C. Martini et al. J. 0187 Sedative Agent: GABA Receptor Modulating Neurochem. 1983, 41, 1183; Lewin, A. H. et al. Mol. Agents Pharmacol. 1989, 35, 189; Schwartz, R. D.; Mindlin, M. C. J. Pharmacol. Exp. Ther: 1988, 244, 963; Facklam, M.; 0188 Y-Aminobutyric acid (GABA) is the major inhibi Bowery, N. G. Br. J. Pharmacol. 1993, 110, 1291; P. tory neurotransmitter in the mammalian central nervous Mathivet et al. Eur: J. Pharmacol. 1992, 321, 67; A. Green system. Receptors for GABA have traditionally been et al. Br. J. Pharmacol. 2000, 131(8), 1766; K. Kaupmann divided into GABA and GABA receptor subtypes. The et al. Nature 1997,386, 239; H. W. Damm et al. Res. Comm. GABA receptor is the more prominent GABA receptor Chem. Pathol. Pharmacol. 1978, 22, 597; and R. C. Speth Subtype, and is a ligand-gated chloride ion channel that is et al. Life Sci. 1979, 24, 351. Furthermore, a representative opened after release of GABA from presynaptic neurons. procedure for determining the binding affinity of a com The GABA receptor is a member of the G protein-coupled pound to a GABA receptor is described below. For addi receptor family coupled both to biochemical pathways and tional details pertaining to the following procedure See U.S. to regulation of ion channels. See Goodman and Gilman's Pat. No. 6,743,789. The Pharmacological Basis of Therapeutics, McGraw-Hill, 0194 The affinity of a compound at GABA-receptor New York, N.Y., 9", Edition, (1996) and Kerr, D. I. B. and subtypes can be measured by competition for HIflumazenil Ong, J. Pharmac. Ther: 1995, 67, 187-246. (85 Ci/mmol; Amersham) binding to SF9 cells expressing 0189 By gating negative chloride ions into the interior of rat receptors of composition C.133y2, C.2fB3y2, C3 B32 and cells, GABA inhibits the presynaptic release of neurotrans C5B3y2. mitter due to a positive Voltage polarization pulse. This form of inhibition is extremely common. For example, GABA 0195 Cellpellets are suspended in Krebs-tris buffer (4.8 receptors can be found in 60-80% of central nervous system mM KCl, 1.2 mM CaCl, 1.2 mM MgCl, 120 mM NaCl, 15 neurons. Subtypes of GABA receptors can be activated by mM Tris; pH 7.5; binding assay buffer), homogenized by the mushroom toxin muscimol (at GABAA) as well as the polytron for ca. 15 sec on ice and centrifuged in UZ for 30 antispasmodic amino acid baclofen (GABA). These com min at 4° C. (100000 g; rotor: TFT 4594=300000 rpm). The pounds directly mimic the action of GABA at the receptor. cellpellets were resuspended in Krebs-tris buffer and Allosteric facilitation of GABA receptorS occurs at Several homogenized by polytron for ca. 15 Sec on ice. Aliquots of distinct Sites, compounds that bind there are used as Seda 1 mL are prepared, protein is measured (Bradford method) tives and anxiolytics. and the resulting membrane aliquots were stored at -70° C. 0190. A characteristic property of GABAA receptors is 0.196 Radioligand binding assays are carried out in a the presence of a number of modulatory Sites, one of which volume of 200 uL (96-well plates) which contained 100 uL is the benzodiazepine (BZ) binding site. The BZ binding site of cells, Hflumazenil at a concentration of 1 nM for is the most explored of the GABAA-receptor modulatory C.1C2C3 subunits and 0.5 nM for C5 subunits and the test Sites, and is the Site through which anxiolytic drugS Such as compound in the range of 10' 3x10 M. In certain temazepam exert their effect. Before the cloning of the instances, nonspecific binding is defined by 10 M diaz GABAA-receptor gene family, the benzodiazepine binding epam. ASSays are incubated to equilibrium for 1 hour at 4 site was historically Subdivided into two subtypes, BZ1 and C. and harvested onto GF/C uni-filters (Packard) by filtra BZ2, on the basis of radioligand binding studies. The BZ1 tion using a Packard harvester and washing with ice-cold Subtype has been shown to be pharmacologically equivalent wash buffer (50 mM Tris; pH 7.5). After drying, filter to a GABAA-receptor comprising the C1-Subunit in combi retained radioactivity was detected by liquid Scintillation nation with a 3-subunit and Y2. This is the most abundant counting. K values are calculated using Excel-Fit GABAA-receptor Subtype, and is believed to represent (MicroSoft) and are the means of two determinations. almost half of all GABAA receptors in the brain. 0197) GABA Receptor Modulating Compounds or 0191 In general, a dose of the GABA-receptor modulat Agents ing agent or a pharmaceutically acceptable Salt thereof 0198 Alarge number of compounds are known to bind to Suitable for administration to a human will be in the range the GABA receptor and modulate the activity of the receptor. of 0.01 to 50 mg per kilogram body weight of the recipient Modulation of the GABA receptor can be agonistic or per day, preferably in the range of 0.1 to 3 mg per kilogram antagonistic. The compound can bind to any part of the body weight per day. Unless otherwise Stated all weights of GABA receptor sufficient to modulate the activity of the US 2005/0176680 A1 Aug. 11, 2005 24 receptor. In certain instances, the GABA-receptor modulat is an anticonvulsant, and it further exhibits muscle relaxant, ing compound binds to a GABAA receptor. In certain anti-aggressive, and anxiolytic activities. instances, the GABA-receptor modulating compound binds to a GABA receptor. In certain embodiments, the GABA 0203 The compound binds to the benzodiazepine recep receptor modulating compound has a Ki of less than about tor complex, or to a site linked closely to this receptor 750 nM in a GABA-receptor binding assay. In certain complex. (See Goa, K. L. and Heel, R. C. Drugs, 32:48-65, embodiments, the GABA-receptor modulating compound (1986); Brun, J. P., Pharmacology, Biochemistry and Behav has a K of less than about 500 nM in a GABA-receptor ior, 29:831-832, (1988); Julou, L. et al., Pharmacology, binding assay. In certain embodiments, the GABA-receptor Biochemistry and Behavior, 23.653-659, (1985); Verma, A. modulating compound has a K of less than about 250 nM in and Snyder S. H., Annu. Rev. Pharmacol. Toxicol, 29:307 a GABA-receptor binding assay. In certain embodiments, 322, (1989). The central benzodiazepine receptor is a mac the GABA-receptor modulating compound has a Ki of leSS romolecular complex that includes a site for the binding of than about 100 nM in a GABA-receptor binding assay. In gamma-aminobutyric acid (GABA), the inhibitory neu certain embodiments, the GABA-receptor modulating com rotransmitter, Suggesting that benzodiazepines and chemi pound has a K of less than about 75 nM in a GABA-receptor cally unrelated agonists including Zopiclone may exert their binding assay. In certain embodiments, the GABA-receptor effects by facilitating the synaptic effects of GABA. While modulating compound has a K of less than about 50 nM in it interacts with the benzodiazepine receptor, Zopiclone a GABA-receptor binding assay. In certain embodiments, apparently has minimal effects on memory, no interaction the GABA-receptor modulating compound has a Ki of leSS with alcohol, and little or no abuse or dependence potential. than about 25 nM in a GABA-receptor binding assay. In 0204. The pharmacologic activity of Zopiclone is pre certain embodiments, the GABA-receptor modulating com dominantly that of a Sedative or hypnotic, particularly at low pound has a K of less than about 15 nM in a GABA-receptor doses. Accordingly, the drug may improve Sleep in adults binding assay. In certain embodiments, Said GABA-receptor and geriatric patients with Several types of sleep disorders, binding assay is a GABAA-receptor binding assay. In certain and Situational, transient, primary, and Secondary insomnia. embodiments, Said GABA-receptor binding assay is a Following a bedtime dose of Zopiclone, there is minimal GABAA-agonist receptor binding assay. In certain embodi impairment of psychomotor Skills and mental acuity the ments, Said GABA-receptor binding assay is a GABAA following morning. The drug is well absorbed from the antagonist receptor binding assay. In certain embodiments, Stomach, and it is not highly bound to plasma proteins. Said GABA-receptor binding assay is a GABAA-benzodi 0205 The racemic mixture of Zopiclone is presently used aZepine receptor binding assay. In certain embodiments, said outside the United States primarily as an hypnotic, improv GABA-receptor binding assay is a GABA-receptor binding ing Sleep patterns in chronic insomniacs and providing Sleep assay. In certain embodiments, Said GABA-receptor binding induction before Surgical procedures in hospitalized assay is a GABA-agonist receptor binding assay. patients. 0199 Importantly, compounds known in the art that 0206 Insomnia is characterized by difficulty in sleeping modulate the activity of the GABA receptor are amenable to or disturbed sleep patterns. Insomnia may be of a primary the present invention. Accordingly, GABA analogs with nature with little apparent relationship to immediate Somatic pharmaceutical activity have been Synthesized and or psychic events, or Secondary to Some acquired pain, described in U.S. Pat. Nos. 4,024,175; 5,563,175; 6,020, anxiety or depression. Where possible, treatment is directed 370; 6,028,214; 6,103,932; and 6,117,906; and International to the underlying cause of the condition; hypnotic medica Patent Applications WO 92/09560, WO 93/23383, WO tion Such as Zopiclone is generally reserved for insomnia of 97/29101, WO 97/33858, WO 97/33859, WO 98/17627, emotional disturbances and for refractory cases due to more WO 99/08671, WO 99/21824, WO 99/31057, WO common causes. In these cases, Zopiclone provides Sedative 99/31074, WO 99/31075, WO 99/61424, WO 00/15611, hypnotic effects from the first day of-treatment, an activity WO 00/31020, and WO 00/50027, each of which is hereby that is maintained following Subsequent doses over long incorporated by reference. In addition, GABAB receptor treatment periods. There appears to be no diminution or agonists are disclosed in EP 0356128; EP 0181833, EP potentiation of activity in adult or geriatric patients, and little O399949, EP 0463969, and FR 2,722,192, each of which is or no effect on alertneSS and performance Some ten hours hereby incorporated by reference. following the bedtime dose. (Brun, J. P. Pharmacology, 0200 Racemic Zopiclone Biochemistry and Behavior 1988, 29, 831-832). 0201 Zopiclone is the first of a chemically distinct class 0207. In addition, the racemic mixture of Zopiclone may of hypnotic and anxiolytic compounds that offers a psycho be useful in treating other disorderS Such as convulsive States therapeutic profile of efficacy and Side effects similar to the like epilepsy. Seizure disorder or epilepsy represents a broad benzodiazepines. This class of compounds, the cyclopyrro group of central nervous System disorders of function that lones, appears to cause leSS residual Sedation and slowing of are characterized by recurrent, Sudden, often brief attacks, reaction times than the benzodiazepines, and it offers the which may alter consciousness, motor activity, Sensory promise of an improved therapeutic indeX over benzodiaz phenomena, and autonomic responses, and which may epines. prompt inappropriate behavior. Recurrent Seizure patterns of either an idiopathic or Symptomatic etiology are termed 0202) The pharmacology of Zopiclone has been shown epilepsy. The most common form of these recurrent but both preclinically and clinically to be characterized by five transient episodes are convulsive Seizures, which may distinct elements. It is predominantly a hypnotic-sedative, include loSS of consciousness, motor function and control, offering Significant activity on first treatment in the absence and which may produce tonic or clonic jerking of the of respiratory or cardiac depression. Additionally, Zopiclone extremities. Pharmacological treatment of epilepsy has been US 2005/0176680 A1 Aug. 11, 2005 25 directed to control based on Seizure type, rather than etiol carboxylate. The chemical Structure of Zopiclone is shown ogy. Accordingly, the convulsions have been grouped in below: broad but rather distinct types including Tonic-clonic (Grand Mal), Partial (Focal) seizures, psychomotor (Complex par tial) seizures, pyknoepileptic or Absence (Petit Mal) and the O less frequent Myoclonic Seizures. N 0208. The binding of Zopiclone at or near the benzodi aZepine receptor complex Suggests that the compound may N \ / C facilitate the inhibitory action of the neurotransmitter GABA and therefore its Synaptic effects. AS Stated above, benzodi O aZepine receptors, which can be located both within the central nervous system and peripherally (e.g., in the endo crine System), are comprised of macromolecular complexes characterized by Sites for binding of the benzodiazepines, GABA, and Zopiclone. The benzodiazepine receptor com pleX is further associated with, and interacts with, a trans membrane channel for chloride ion transport. The effect of Zopiclone's interaction with the benzodiazepine receptor/ GABA receptor/chloride channel complex is to cause GABA 0214 ESzopiclone is an optical isomer, the (+)-isomer, of to inhibit cerebral neuronal discharge, presumably by the compound zopiclone, which is described in U.S. Pat. increasing membrane conductance of chloride ion, thus Nos. 6,319,926 and 6,444,673, and in Goa and Heel, Drugs, Stabilizing membrane potentials and dampening excitatory 32:48-65 (1986) and in U.S. Pat. Nos. 3,862,149 and input. (See Meldrum, B. S., Brit. J. Clin. Pharm., 27 (Suppl. 4,220,646. This isomer, which will hereinafter be referred to 1): 3S-11S, (1989)). It is believed that through mediation of as eSZopiclone, includes optically pure and the Substantially this process Zopiclone may be useful in treating epilepsy and optically pure (e.g., 90%, 95% or 99% optical purity) a number of other conditions in which GABA is believed to (+)-Zopiclone isomer. exert a physiologic role. 0215 Racemic Zopiclone is commercially available and 0209 While the racemic mixture of Zopiclone may be can be made using various methods, Such as those disclosed useful in the treatment of the above-described disorders, it in U.S. Pat. Nos. 3,862,149 and 4,220,646. ESzopiclone may has a low therapeutic indeX and also causes adverse effects. be prepared from racemic Zopiclone using Standard meth These adverse effects include, but are not limited to, the ods, Such as chiral-phase chromatography, resolution of an development of a bitter taste due to the Salivary Secretion of optically active Salt, Stereoselective enzymatic catalysis by the drug, dry mouth, drowsiness, morning tiredness, head means of an appropriate microorganism, or asymmetric ache, dizziness, impairment of psychomotor skills and synthesis. U.S. Pat. No. 6,319,926 discloses methods for related effects. making eSZopiclone, including resolution from racemic 0210. It has recently been discovered that by using opti Zopiclone by means of an optically active acid, Such as cally pure or Substantially optically pure (+) Zopiclone yields D(+)-O,O'-dibenzoyltartaric acid. an increase in the potency of therapeutic effect as compared 0216) Another method for making esZopiclone (or (S)- to that found in the racemic mixture. In addition, utilizing Zopiclone) is by Synthesis from racemic Zopiclone (or (RS)- the optically pure isomer of (+) Zopiclone results in clearer Zopiclone) by chemical resolution via the D-malate Salt as dose-related definitions of efficacy, diminished adverse shown in the following Synthesis Schematic. effects, and accordingly, an improved therapeutic index. Hence, it is generally more desirable to use the (+) isomer of Zopiclone. 0211 ESzopiclone D-Malic Acid 0212 ESzopiclone (or (+)-Zopiclone or (S)-Zopiclone) is Acetone/MeOH Resolution a potent drug useful for the treatment of Sleep disorders, s NF He convulsive disorders, and disorders that are affected by the binding of agonists to central nervous System or peripheral benzodiazepine receptors. Administration of isomerically "Sc-N N-CH pure or substantially isomerically pure (e.g., 90%, 95%, or | \ / 99% isomeric purity) (+)-Zopiclone is generally preferred because this isomer possesses potent activity in treating (RS)-Zopiclone Sleep disorders while avoiding adverse effects including but O not limited to drowsiness, next day effects, Such as tiredneSS eN in the morning, inability to concentrate and headache. C N -(-)- C COOH (basification) n NF o OH RAI 0213 ESzopiclone is a cyclopyrrolone that has the chemi O / v . IVILIlling YC-N N-CH, CH3COOH cal name (+) 6-(5-chloro-pyri-2-dyl)-5-(4-methylpiperazin I V / 1-yl)carbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo3-4b) O pyrazin or (+) 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo (S)-Zopiclone D-Malate 5H-pyrrolo3.4bpyrazin-5-yl 4-methylpiperazine-1- US 2005/0176680 A1 Aug. 11, 2005 26

affected by the binding of agonists to central nervous System -continued and peripheral benzodiazepine receptors. Such disorders O include but are not limited to aggressive behavior, muscle tension, behavioral disorders, depression, Schizophrenia, 2^ and disorders associated with abnormal plasma hormone levels Such as endocrine disorders. These compositions are s NF useful in treating disorders that are affected by the binding of agonists to central nervous System and peripheral benzo On ? V diazepine receptorS. C-N N-CH 0222. The size of a prophylactic or therapeutic dose of \ / eSZopiclone in the acute or chronic management of disease Eszopiclone will vary with the severity of the condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, 0217. In the synthetic route shown above, (RS)-Zopi and response of the individual patient. In general, the total clone and D-malic acid are dissolved in a mixture of acetone daily dose ranges, for the conditions described herein, is and methanol to form (S)-Zopiclone D-malate and (R)- from about 0.25 mg to about 15 mg. Preferably, a daily dose Zopiclone D-malate. The two diastereomeric Salts are range should be between about 0.5 mg to about 10 mg. Most resolved in-situ by Selective crystallization, filtration and preferably, a daily dose range should be between about 1.0 rinsing to produce highly (S)-enriched Zopiclone D-malate mg to about 5.0 mg. In managing the patient, the therapy salt. In this process, the majority of (R)-Zopiclone D-malate may be initiated at a lower dose, perhaps about 0.5 mg to remains in the mother liquors. In this method, the use of an about 3 mg and increased up to about 5 mg or higher acetone/methanol co-Solvent System results in a highly dias depending-on the patient's global response. It is further tereoselective Salt crystallization, and preferably, the co recommended that children and patients over 65 years, and Solvent ratio used should be in the range of approximately those with impaired renal or hepatic function, initially 1.9/1 to 2.3/1 w/w acetone in methanol. Preferably, this stage receive low doses, and that they be titrated based on global of the process may also include cooling the reaction mixture response and blood level. It may be necessary to use dosages during the isolation Step to a temperature in the inclusive outside these ranges in Some cases. range of about 10 C. to 15 C., and washing or rinsing the wet cake obtained after filtration with cold Solvent, such as 0223) In the case where an oral composition is employed, cold methanol. a Suitable dosage range for use is from about 0.25 mg to about 15.0 mg with, in the usual case, the lower doses 0218. The resulting (S)-Zopiclone D-malate salt is con Serving more common insomnia, and the higher doses, verted to optically pure eSZopiclone free base by treatment presented in divided dosing, reserved for control of psychi with aqueous potassium carbonate and ethyl acetate, fol atric disorders. Preferably, a dose range of between about 0.5 lowed by phase Separation and crystallization. In this pro mg to about 10 mg is given as a once daily administration ceSS, once a Solution of eSZopiclone free-base is obtained, or in divided doses if required; most preferably, a dose range additional enantiomeric enrichment (typically 1 to 4%) can of from about 1.0 mg to about 5 mg is given, either as a once be achieved by crystallization from ethyl acetate of low daily administration or in divided doses if required. Patients water content. The water content can be controlled, e.g., by may be upward titrated from below to within this dose range azeotropic distillation, and incorporating an in-proceSS con to a Satisfactory control of Symptoms as appropriate. trol of water content into the crystallization process can further improve the robustness of enantiomeric purity. Pref 0224. The pharmacologic profile of hypnotic-sedative erably, the water level during this Step is 2% or less, more agents of the benzodiazepine class has been rather well preferably 1% or less, and most preferably 0.6% or less. established (Goodman and Gilman: The Pharmacological Basis of Therapeutics, 7th. Edition, Chapt. 17, 340-351, 0219. The resulting optically pure eszopiclone free base (1985), MacMillan Publishing Co., N.Y.) and has been can then be milled to a desired size for use as an active extended to non-benzodiazepine agents of the cyclopyr ingredient in a pharmaceutical composition according to or rolone class (Bardone, M. C. et al., Abstract No. 2319, 7th. for use in methods of the present invention. This two-stage Int. Congr. Pharm. Paris, July, 1978, Pergamon Press, Lon process is depicted in the diagrams of FIGS. 1 and 2. don; Julou, L. et al., Pharmacology, Biochemistry and 0220 ESzopiclone possess potent activity in treating Behavior, 23:653-659 (1985)). Accordingly, a variety of Sleep disorderS Such as insomnia. ESZopiclone also possess experimental models, which are rather well characterized potent activity in treating Sleep disorders while avoiding the (Julou, L. et al., ibid, 1985) can be used to characterize the usual adverse effects including but not limited to drowsiness, various activities of Zopiclone, its anticonvulsant, myore next day effects tiredness in the morning, inability to con laxant, anti-aggressive, and Sedative-hypnotic activities. In centrate and headache, which are associated with the admin an examination of each element of the pharmacologic pro istration of the racemic mixture of Zopiclone. ESZopiclone file, the activity of a pharmaceutical composition comprising also possess potent activity in treating convulsive disorders Zopiclone can be compared and contrasted with Such phar Such as epilepsy while avoiding the adverse effects which macologic Standards as nitrazepam and diazepam, two ben are associated with the administration of the racemic mix Zodiazepine agents, in a variety of animal models. The dose ture of Zopiclone. (mg/kg) of each agent that is capable of inhibiting by 50% (the IDso or EDso) an induced response in rodents, for 0221) Additionally, compositions containing optically example, provides the basis for comparison. Thus, pentyle pure eSZopiclone are useful in treating disorders that are netetrazole-induced convulsions, picrotoxin convulsions, US 2005/0176680 A1 Aug. 11, 2005 27 and electrically-induced convulsions can be used to dem

onstrate the anti-convulsant activity of Zopiclone (Haefely, W., Psychotropic Agents, eds. Hofmeister, F. and Stille, G., Springer Verlag, Berlin, Part 11, 12-262, (1981)). Further, in the rat, in the amygdala kindled model of epilepsy, daily electrical Stimulation of the amygdala induces a progressive increase of epileptic afterdischarge duration, with increasing epileptic behavioral Symptoms, producing in Some two weeks a generalized convulsive crisis. Presumably, previ ously ineffective Stimuli have Sensitized neuronal pathways, and it has been Suggested that a similar mechanism may exist for the induction of an anxiety State in man after 0229 Indiplon occurs as an off-white to yellow, non-free repeated Stresses. flowing powder with little Static charge. The compound is 0225. Similar models are available for determination of lipid soluble (log D partition coefficient=1.73), and is the myorelaxant, anti-aggressive, and Sedative-hypnotic soluble in water at approximately 20-30.mu.g/mL with a activities of pharmaceutical compositions comprising Zopi resulting pH of approximately 8.0. Indiplon may be prepared clone and its optically pure enantiomers in both mice and using chemical Synthesis techniques known to those skilled rats. (For review see Julou, L. et al., ibid, 1985.) The acute in this field. For example, Indiplon may generally be made toxicity of a pharmaceutical composition comprising Zopi by the synthetic procedures disclosed in U.S. Pat. Nos. clone or eSZopiclone can be determined in Studies in which 4,521,422 and 4,900,836. These patents, particularly U.S. rats are administered at progressively higher doses (mg/kg) Pat. No. 4,521,422, disclose a genus encompassing certain of pharmaceutical composition. That lethal dose which, aryl and heteroaryl7-(aryl and heteroaryl)-pyrazolo15-all when administered orally, causes death of 50% of the test pyrimidin-3-yl)methanones. animals, is reported as the LDso. 0230. The size of a prophylactic or therapeutic dose of 0226. The effects of a pharmaceutical composition on Indiplon in the acute or chronic management of disease will Psychomotor Behavior can be determined by measuring ten vary with the severity of the condition to be treated and the parameters (pinna reflex, Spontaneous activity, palpebral route of administration. The dose, and perhaps the dose Size, startle response, touch response, reactivity, placing, frequency, will also vary according to the age, body weight, righting reflex, exploration, and ataxia). Each parameter and response of the individual patient. In general, the total scores 2 points for normalcy for a total of 20 pointsx3 daily dose ranges, for the conditions described herein, is mice=60 points possible. Scores below 40 (<40) denote from about 1 mg to about 75 mg. Preferably, a daily dose behavioral deprSesion. Scores are determined before and range should be between about 5 mg to about 50 mg. Most after dosing with test Sample. See Irwin, S., Psychophar preferably, a daily dose range should be between about 10 mg to about 35 mg. In certain embodiments, the daily dose rmacologia, 13:222-257 (1968). range should be about 10, 25, 30, or 35 mg. In managing the patient, the therapy may be initiated at a lower dose, perhaps about 2 mg to about 5 mg and increased up to about 10 mg REFERENCE AGENTS (ED, mg/kg) or higher depending-on the patient's global response. chlordiazepoxide 1OO 0231. The mean plasma half-life of a sedative-hypnotic chlorpromazine 25 compound may be determined using well known techniques. clozapine 25 diazepam 50 Terminal half-life may be determined using Standard phar glutethimide 3OO macokinetic calculations, Such as those presented by haloperidol 1O Rolland and Tozer (Clinical Pharmacokinetics Concepts and meprobamate 3OO Applications, 3" Ed., Chap. 3, 1995). in addition, software pentobarbital 1OO phenobarbital 150 is commercially available which performs this calculation, reserpine 50 such as the product sold under the tradename “WinNinlinTM' thioridazine 50 (Prof. Ver. 1.5). This software calculates terminal plasma half-life (t) from the following relationship: “t=1n(2)/ lambda”, wherein “1n(2)” is the natural log of 2 and 0227 Indiplon "lambda..' is the first order rate constant associated with the terminal (log-linear) portion of the plasma test compound 0228 Indiplon is a potent sedative, anxiolytic and anti concentration: time profile. This is estimated by linear convulsant agent, and possesses an improved profile of Side regression analysis of the time VS. log concentration of the effects, as compared to other benzodiazepine agents. test compound. Indiplon shows a reduced tolerance to Sedation, a lowered potential for abuse and a reduced tendency to potentiate the 0232 The sedative-hypnotic effect of a compound may deleterious effects of ethanol. In addition, Indiplon appears be readily established using, for example, Standard tests that to be Substantially devoid of next-day hangover effects and monitor the effects of a drug on motor activity, muscle to have a considerably reduced amnesic potential compared relaxation and motor coordination (see, e.g., Beer et al., to currently marketed Sedative-hypnotic agents. The half-life CNS Drug Reviews 3:207-224, 1997; Sanger et al., Eur. J. of indiplon in Vivio is approximately 1.3 hours. Indiplon has Pharmacol. 313:35-42, 1996, and references cited therein). the chemical name N-methyl-N-(3-3-2-thienylcarbonyl In general, a Sedative-hypnotic compound should have a pyrazolo-1,5-a-pyrimidin-7-yl)-phenyl)acetamide and is Statistically significant Sedative effect within at least one, represented by the formula below: and preferably all, of the following assays: (a) assays to US 2005/0176680 A1 Aug. 11, 2005 28 detect a reduction in locomotor activity, as described by demonstrates linear kinetics in the therapeutical dose range, Sanger et al., European J Pharmacol. 313:35-42, 1996 and which lies between 5 and 10 mg in conventional forms, peak Beer et al., CNS Drug Reviews 3:207-224, 1997; (b) assays plasma concentration is reached at between 0.5 and 3 hours, to detect an increase in total Sleep time, as determined by the elimination half-life is short, with a mean of 2.4 hours electroencephalographic (EEG) measures, as described in and a duration of action of up to 6 hours. Generally, the Beer et al., CNS Drug Reviews 3:207-224, 1997; and (c) dosage of Zolpidem is between 1 and 50 mg. assays to detect a reduction in motor coordination, as defined 0238 Traditionally, only immediate release dosage forms by a reduced latency to remain on a rotating rod and/or a were developed which disintegrated rapidly in the gas reduction in alertness, or Vigilance (both assays as described trointestinal tract, dissolved in the fluid of the gastrointes by Sanger et al., European J Pharmacol. 313:35-42, 1996 tinal tract and underwent Systemic absorption, where Zolpi and Beer et al., CNS Drug Reviews 3:207-224, 1997). dem, can exert its pharmacological effect and induce Sleep 0233 Zolpidem of the patient. More recently, new dosage forms have been developed which Sustain release of Zolpidem over a period 0234 Zolpidem is a hypnotic agent that is known to compatible with the desired time of sleep and the time induce or maintain Sleep. Zolpidem is an imidazopyridine needed for elimination of the drug from the human body to having IUPAC chemical nomenclature N,N,6-trimethyl-2- a sufficiently low level. See U.S. Pat. Nos. 6,638,535 and (4-methylphenyl)-imidazol,2-Spyridine-3-acetamide. The 6,514,531. Structure of Zolpidem is presented below. 0239). The pharmacological effect of the Zolpidem can be evaluated using the biological assays described in U.S. Pat. No. 4,382.938. For example, the toxicity of a compound can 21Ne.N. be determined on mice by intraperitoneal administration using LD50 ranges from 500 to 1,000 mg/kg. In addition, N-N/ the anxiolytic activity can be determined according to the eating test (R.J. Stephens, (1973), Brit. J. Pharmac., 49, 146 O P). In this test, the doses which increases the food consump tion of the mice vary from 0.1 to 10 mg/kg, administered N intraperitoneally. 0240 The activity of the compounds in the area of cerebral circulation can be determined in the test for the hypoxia caused by pressure reduction. Mice of the CD1 0235. The Zolpidem free base was disclosed generically Strain are kept in an oxygen-depleted atmosphere produced in EP 50563 of Synthelabo. Zolpidem tartrate was subse by creating a partial vacuum (190 mm of mercury, corre quently disclosed in EP 251859 (U.S. Pat. No. 4,794.185). sponding to 5.25% of oxygen). The Survival time of the More recently, Zolpidem has been Suggested as useful in animals is noted. This time is increased by agents which are treating Parkinson's disease, parkinsonian Symptoms, obses capable of assisting the oxygenation of tissues and in Sive-compulsive disorder and certain forms of dementia in particular of the brain. The compounds Studied are admin U.S. Pat. No. 5,891,891. istered intraperitoneally in Several doses, 10 minutes before 0236 Zolpidem has been marketed as an immediate the experiment. The percentage increases in the Survival release tablet for oral application under the trade marks time, relative to the values obtained for control animals, are AMBIENCE) and STILNOXCE). In these commercial pharma calculated. The mean active dose (MAD), that is to say the ceutical dosage forms, Zolpidem is present as a Salt with dose which increases the survival time by 100%, is deter L(+)tartaric acid wherein the molar ratio of Zolpidem to mined graphically. tartaric acid is 2:1. This Salt is conventionally called Zolpi 0241 The anticonvulsant activity can be determined in dem hemitartrate but a more correct denomination thereof, accordance with the test for the antagonism towards the which will be used hereinafter, is Zolpidem tartrate. The mortality induced by bicuculline in mice (P. Worms, H. European Pharmacopoeia, Monograph No. 1999:1280, Depoortere and K. G. Lloyd, (1979) Life Sci., 25, 607-614). States that Zolpidem tartrate is characterized as a white or The products to be studied are injected intraperitoneally, 30 almost white crystalline powder, hygroscopic, Slightly minutes before the bicuculline (0.9 mg/kg, administered Soluble in water, Sparingly Soluble in methanol, and practi intravenously). With death being the criterion selected for cally insoluble in methylene chloride. Commercially avail this test, the percentage mortalities are noted for each batch, able Zolpidem tablets are conventional film coated tablets for 2 hours after administration of the bicuculline (control immediate release of the active Substance after ingestion and batch: 100% mortality). For each product, the 50% active they contain 5 or 10 mg of Zolpidem tartrate. The inactive dose (AD 50 or the dose which protects 50% of the animals ingredients are: lactose, microcrystalline cellulose, Sodium from the lethal effects of the bicuculline) is determined Starch glycolate, hydroxypropylmethylcellulose and magne graphically. sium Stearate. The film coating layer consists of hydrox ypropylmethylcellulose, polyethylene glycol and colorants. 0242. The sedative or hypnotic activity can be deter mined by observing the action of the compounds on the EEG 0237 Zolpidem is generally administrated orally by of curarised rats and also on the wake-sleep States in freely means of a tablet or other Solid dosage form. Indeed phar moving, implanted rats and cats (H. Depoortere, Rev. E. E. macokinetic and pharmacodynamic data show that Zolpidem G. Neurophysiol., (1980) 10, 3, 207-214; L. M. Da Costa, H. has both a rapid absorption and onset of hypnotic action. Its Depoortere and R. Naquet, Rev. E. E. G. Neurophysiol., bioavailability is 70% following oral administration and (1977), 7, 2, 158-164). In curarised rats, the products to be US 2005/0176680 A1 Aug. 11, 2005 29

Studied are injected intraperitoneally or orally at doses vary with the severity of the condition to be treated and the increasing from 0.1 to 30 mg/kg. In freely moving, route of administration. The dose, and perhaps the dose implanted rats, the products to be Studied were injected frequency, will also vary according to the age, body weight, intraperitoneally or orally at a single dose ranging from 1 to and response of the individual patient. In general, the total 10 mg/kg. In freely moving, implanted cats, the products to daily dose ranges, for the conditions described herein, is be studied were injected intraperitoneally or orally at a from about 1 mg to about 50 mg. Preferably, a daily dose Single dose of 10 mg/kg. range should be between about 1 mg to about 25 mg. Most preferably, a daily dose range should be between about 5 mg 0243 The results of these various tests can be used to to about 20 mg. In certain embodiments, the daily dose range determine the anti-anoxic, Sleep-inducing, hypnotic and should be about 5, 10, 15, or 20 mg. In managing the patient, anticonvulsant properties of a pharmaceutical composition. the therapy may be initiated at a lower dose, perhaps about 0244 Zaleplon 2 mg to about 5 mg and increased up to about 10 mg or 0245 Zaleplon (Wyeth-Ayerst), also known as “Sonata”, higher depending-on the patient's global response. is a nonbenzodiazipine recently approved by the FDA as 0249 Generally, Zaleplon should be taken just prior to sedative-hypnotic (see U.S. Pat. No. 4,626.538). Zaleplon is bedtime or immediately if a patient the patient has already a pyrazolopyrimidine that has the chemical name N-3-(3- gone to bed is having diffuculty falling asleep. In certain cyanopyrazolo 1.5-apyrimidin-7-yl)phenyl-N-ethylaceta instances the dose of Zaleplon should be adjusted in accord mide. Zaleplon is a white powder that has very low Solu with diet or Special needs of the patient. For example, the bility in water and limited solubility in alcohol or propylene dosage of Zaleplon should be approximately 5 mg for glycol. The Structure of Zaleplon is given below. elderly or debilitated patients whom are likely to be par ticularly Sensitive to hypnotic medications. In addition,

patients Suffering from mild to moderate hepatic impairment should be administered only a 5 mg dose because Systemic removal of drug is reduced in Such patients. 0250 Gaboxadol 0251 Gaboxadol is a GABA-receptor agonist that has been shown to improve sleep-quality in both human and animal studies. Procedures for the preparation of gaboxadol have been described. U.S. Pat. No. 4,278,676; and P. Krogs gaard-Larsen, Acta. Chem. Scand. 1977, 31, 584. Gaboxa dol, also known as THIP, is a crystalline, colorless solid that is soluble in water and methanol. The chemical name for gaboxadol is 4,5,6,7-tetrahydroisoxazolo5,4-cpyridin-3- ol. Gaboxadol is known to exist in two isomeric forms (Form A and Form B, shown below) and the term "gaboxa dol' as used herein encompasses both forms Separately, a 0246 Zaleplon binds to the gamma-aminobutyric acid mixture comprising both isomeric forms, and the pharma benzodiazepine (GABA-BZ) receptor complex. Binding ceutically acceptable Salts of any of them. studies have revealed that Zaleplon binds selectively to the brain omega-I receptor located on alpha Subunit of the GABAA/chloride ion channel receptor complex. This inter A. action modulates the binding of t-butylbicyclophospho OH rothionate binding. Importantly, the pharmacological prop erties of benzodiazepines, e.g. Sedative, anxiolytic, muscle relaxant, and anticonvulsive effects in animals, are linked to N modulation of the GABA-BZ receptor chloride channel H1 O N complex. B 0247 The pharmacokinetic profile of Zaleplon has been O investigated in trials using a 60 mg Single dose and once daily administration of a 15 or 30 mg dose for up to 10 days. The data indicate that pharmacokinetics are proportional to H-N N the dose throughout the therapeutic range. In addition, 1. O Zaleplon does not accumulate in once-daily administration treatment regimes. Zaleplon is rapidly absorbed when 0252) The GABA-receptor binding affinity and pharma administered orally; however, Zaleplon is Subject to Sub cological properties of gabOXadol have been described. U.S. stantial presystemic metabolism resulting in only 30% bio Pat. No. 4,278,676. In order to study the interactions of availability. The majority of the metabolism is attributed to gaboxadol with the central GABA receptors in vitro, an aldehyde oxidase which converts Zaleplon to 5-OXO gaboXadol was tested in affinity binding experiments. See S. Zaleplon. Consequently, peak plasma concentrations follow J. Enna and S. H. Snyder, Brain Res. 1975, 100, 81-97. The ing oral administration typically occur 1 hour after admin ICso value of gaboxadol was determined to be 0.13+0.005 istration. tiM based on experiments using five different concentrations 0248. The size of a prophylactic or therapeutic dose of of gabOXadol. Each experiment was conducted in triplicate Zaleplon in the acute or chronic management of disease will and the ICs value was determined by logprobit analysis. US 2005/0176680 A1 Aug. 11, 2005 30

0253) In order to study the interactions of gaboxadol with properties are described in Hudgson, Weightman Brit. Med. the central GABA receptors in Vivo, gaboxadol was tested in J. 1971, 4, 15 and S. Ahuja in Analytical Profiles of Drug microelectrophoretic experiments. See U.S. Pat. No. 4.278, Substances vol. 14, K. Florey, Ed. (Academic Press, New 676. Experiments were performed on lumbar dorsal horn York, 1985) pp 527-548. The structure of baclofen is pre interneurones and Renshaw cells of cats anaesthetized with sented below. pentobarbitone sodium. Gaboxadol was found to be rela tively more potent than GABA on the basis of electro phoretic currents required to produce equal and Submaximal inhibitions of the firing of the central neurones. The inhibi tory action of gaboxadol on central neurones was reversibly antagonized by the Specific GABA antagonist bicuculline CO2H methochloride (BMC). Interestingly, gaboxadol did not interact with the GABA uptake System at concentrations of 5x10" M, and it did not interact with the GABA metaboliz Cl ing enzymes GABA:2-oxo-glutarate aminotransferase and L-glutamate 1-carboxylase at concentrations of 10 M. 0259. The size of a prophylactic or therapeutic dose of Based on the above-mentioned experiments, gabOXadol is a baclofen, or one of its Salts, in the acute or chronic man Specific and very potent GABA agonist. For additional agement of disease will vary with the severity of the information regarding the GABA receptor binding proper condition to be treated and the route of administration. The ties of gaboxadol, See: P. Krogsgaard-Larsen et al. Nature dose, and perhaps the dose frequency, will also vary accord 1977, 268, 53. ing to the age, body weight, and response of the individual 0254 The results from toxicity tests indicate that gaboxa patient. In general, the total daily dose ranges, for the dol is less toxic than muscimol. The hydrobromide salt of conditions described herein, is from about 5 mg to about 250 gaboxadol has a LD.so (mg/kg) of 80 (i.v.), 145 (i.p.), and mg. Preferably, a daily dose range should be between about >320 (p.o.) in mice. In comparison, muscimol has a LDso 20 mg to about 150 mg. Most preferably, a daily dose range (mg/kg) of 7 (i.v.), 12 (i.p.), and 22 (p.o.) in mice. See U.S. should be between about 30 mg to about 100 mg. In certain Pat. No. 4,278,676. embodiments, the daily dose range should be about 40, 50, 0255. Several studies have verified that gaboxadol can 60, 70, or 80 mg. In managing the patient, the therapy may improve sleep quality. Lancel and coworkers conducted a be initiated at a lower dose, perhaps about 5 mg to about 15 double-blind, placebo-controlled study in healthy, elderly mg and increased up to about 35 mg or higher depending on patients which revealed that oral administration of gabOxa the patient's global response. In general, children are admin dol can increase Sleep consolidation and the intensity of istered a dosage in the range of about 40, 50 or 60 mg per non-REM sleep. See Lancel, M.; Wetter, T. C.; Steiger, A.; day, often times in divided dosages. Mathias, S. Am. J. Physiol. Endocrinol. Metab. 2001, 281, 0260 Bicuculline E130. In a post-nap Sleep Study, Mathias and coworkers found that gaboxadol facilitates falling asleep while increas 0261 Bicuculline is a naturally occurring GABA antago ing the total sleep time and promoting deep sleep. Mathias, nist. Procedures for the preparation of bicuculline are S.; Steiger, A.; Lancel, M. Psychopharmacology (Berl.) described in Groenewoud, Robinson J. Chem. Soc. 1936, 2001, 157, 299. For additional studies relating to therapeutic 199 and Haworth et al. Nature 1950, 165, 529. The phar uses for gaboxadol see U.S. Pat. No. 5,929,065; Christensen macological properties are described in Curtis et al. Nature et al. Pharm. Weekbl., Scie. Ed. 1982, 4, 145; and S. 1970, 226, 1222. In general, the total daily dose range is Korsgaard et al. Arch. Gen. Psychiatry 1982, 39, 1017. from about 1 mg to about 2000 mg. Preferably, a daily dose range should be between about 5 mg to about 1000 mg. 0256 The size of a prophylactic or therapeutic dose of More preferably, a daily dose range should be between about gaboxadol will vary with the severity of the condition to be 10 mg to about 250 mg. Bicuculline has the chemical name treated and the route of administration. The dose, and (6R)-6-(5S)-5,6,7,8-tetahydro-6-methyl-1,3-dioxolo4.5-g perhaps the dose frequency, will also vary according to the isoquinolin-5-ylfuro3,4-e1,3-benzodioxol-8(6H)-one and age, body weight, and response of the individual patient. In the Structure is presented below. general, the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 90 mg. Preferably, a daily dose range should be between about 2 mg to about 40 mg. Most preferably, a daily dose range should be between about 5 mg to about 30 mg. In certain embodi ments, the daily dose range should be about 10, 15, 20, or 25 mg. In managing the patient, the therapy may be initiated at a lower dose, perhaps about 2 mg to about 4 mg and increased up to about 10 mg or higher depending-on the patient's global response. 0257 Baclofen 0258 Baclofen is a GABA-receptor agonist that has the chemical name f3-(aminomethyl)-4-chlorobenzenepropanoic acid. Procedures for the preparation of baclofen are 0262 CACA is a GABA receptor agonist that has the described in U.S. Pat. No. 3,471,548. The pharmacological chemical name cis-4-aminocrotonic acid. CACA can be US 2005/0176680 A1 Aug. 11, 2005

purchased from Tocris Cookson Inc. in Ellisville, Mo. The described in Lingenhoehl, Olpe Pharmacol. Comm. 1993, 3, pharmacological properties are described in J. Ulloor et al. 49. In general, the total daily dose range is from about 1 mg J. Neurophysiol. 2004, 91(4), 1822-31. In general, the total to about 2000 mg. Preferably, a daily dose range should be daily dose range is from about 1 mg to about 2000 mg. between about 5 mg to about 1000 mg. More preferably, a Preferably, a daily dose range should be between about 5 mg daily dose range should be between about 10 mg to about to about 1000 mg. More preferably, a daily dose range 250 mg. The structure of CGP 46.381 is presented below. should be between about 10 mg to about 250 mg. The structure of CACA is presented below. O 2NS-1)n- HO

0263 B-CCP 0269 CGP 52432 0264 B-CCP is an inverse agonist of the GABA receptor. 0270 CGP52432 is a GABA-receptor antagonist that has B-CCP can be purchased from Tocris Cookson Inc. in the chemical name 3-(3,4-dichlorophenyl)methylamino Ellisville, Mo. The pharmacological properties are described propyldiethoxymethyl)phosphinic acid. CGP52432 can be in P. Polcet al. Epilepsia 1996, 37(10), 1007-14. In general, purchased from KOMA Biotech, Inc. The pharmacological the total daily dose range is from about 1 mg to about 2000 properties are described in Lanza et al. Eur: J Pharmacol. mg. Preferably, a daily dose range should be between about 1993, 237, 191; Froestlet al. Pharmacol. Rev. Comm. 1996, 5 mg to about 1000 mg. More preferably, a daily dose range 8, 127; Bonanno et al. Eur: J. Pharmacol. 1998, 362, 143; should be between about 10 mg to about 250 mg. The and Libri et al. Naunyn-Schmied. Arch. Pharmacol. 1998, structure of B-CCP is presented below. 358, 168. In general, the total daily dose range is from about 1 mg to about 2000 mg. Preferably, a daily dose range should be between about 5 mg to about 1000 mg. More O preferably, a daily dose range should be between about 10 mg to about 250 mg. The structure of CGP 52432 is presented below.

N 2N C CUC1n-1H O H C N-1N1 P OEt 0265 CGP 35348 HO 0266 CGP35348 is a GABA-receptor antagonist that has OEt the chemical name 3-(aminopropyl)(diethoxymeth yl)phosphinic acid. CGP 35348 can be purchased from Tocris Cookson Inc. in Ellisville, Mo. The pharmacological 0271 CGP 54626 properties are described in Olpe et al. Eur: J. Pharmacol. 0272 CGP54626 is a GABA-receptor antagonist that has 1990, 187, 27; Hao et al. Neurosci. Lett. 1994, 182,299; and the chemical name S-(R*,R)-3-1-(3,4-dichlorophenyl Froestl et al. Pharmacol. Rev. Comm. 1996, 8, 127. In )ethylamino-2-hydroxypropyl(cyclohexylmethyl)phos general, the total daily dose range is from about 1 mg to phinic acid. CGP 52432 can be purchased from KOMA about 2000 mg. Preferably, a daily dose range should be Biotech, Inc. The pharmacological properties are described between about 5 mg to about 1000 mg. More preferably, a in Brugger et al. Eur: J Pharmacol. 1993, 235, 153; Froestl daily dose range should be between about 10 mg to about et al. Pharmacol. Rev. Comm. 1996, 8, 127; and Kaupmann 250 mg. The structure of CGP 35348 is presented below. et al. Nature 1998, 396, 683. In general, the total daily dose range is from about 1 mg to about 2000 mg. Preferably, a daily dose range should be between about 5 mg to about O 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg. The structure of CGP 2NN-1N1 OEt 54626 is presented below. HO OEt C H 0267 CGP 46381 t 0268 CGP46381 is a GABA-receptor antagonist that has C nu1N1 the chemical name (3-aminopropyl)(cyclohexylmeth yl)phosphinic acid. CGP 46.381 can be purchased from KOMA Biotech, Inc. The pharmacological properties are US 2005/0176680 A1 Aug. 11, 2005 32

0273) CGP 55845 at a lower dose, perhaps about 1.5 mg to about 3.0 mg and 0274 CGP55845 is a GABA-receptor antagonist that has increased up to about 6 mg or higher depending on the the chemical name (2S)-3-(1S)-1-(3,4-dichlorophenyl patient's global response. )ethylamino-2-hydroxypropyl(phenylmethyl)phosphinic acid. CGP 55845 can be purchased from KOMA Biotech, 0278 Diazepam Inc. The pharmacological properties are described in Davies 0279 Diazepam is a benzodiazepine used to relieve anxi et al. Neuropharmacology 1993, 32, 1071; Froestl et al. Pharmacol. Rev. Comm. 1996, 8, 127; and Deisz Neuro ety, nervousness, and tension associated with anxiety disor Science 1999, 93, 1241. In general, the total daily dose range ders. In addition, diazepam is used to treat certain Seizure is from about 1 mg to about 2000 mg. Preferably, a daily disorders and muscle Spasms. Procedures for the preparation dose range should be between about 5 mg to about 1000 mg. of diazepam are described in U.S. Pat. Nos. 3,371,085; More preferably, a daily dose range should be between about 3,109,843; and 3,136,815. The pharmacological properties 10 mg to about 250 mg. The structure of CGP 55845 is are described in Hudson, Wolpert Arch. Int. Pharmacodyn. presented below. Ther: 1970, 186, 388; M. Mandelli et al. Clin. Pharmacoki net. 1978, 3, 72; and A. MacDonald et al. Anal. Profiles Drug Subs. 1972, 1, 79-99. Diazepam has the chemical H name 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-ben 11 Zodiazepin-2-one and the Structure is presented below. OH |

Cl

C C eN 0275) Clonazepam 0276 Clonazepam is an antianxiety agent marketed under the tradename KLONOPINCE). Procedures for the preparation of clonazepam are described in U.S. Pat. Nos. O 3,121,076 and 3,116,203. The pharmacological properties are described in Guerrero-Figueroa et al. Curr. Ther. Res. Clin. Exp. 1969, 11, 40 and W. C. Winslow Anal. Profiles 0280 The size of a prophylactic or therapeutic dose of Drug Subs. 1977, 6, 61-81. Clonazepam has the chemical diazepam, or one of its Salts, in the acute or chronic name 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-ben management of disease will vary with the Severity of the Zodiazepin-2-one and the Structure is presented below. condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary accord ing to the age, body weight, and response of the individual patient. In general, the total daily dose ranges, for the conditions described herein, is from about 0.5 mg to about 200 mg. Preferably, a daily dose range should be between about 1 mg to about 100 mg. Most preferably, a daily dose ON eN range should be between about 5 mg to about 40 mg. In certain embodiments, the daily dose range should be about 10, 15, 20, 25, 30 or 35 mg. In managing the patient, the therapy may be initiated at a lower dose, perhaps about 3 mg O to about 4 mg and increased up to about 12 mg or higher depending on the patient's global response. 0277. The size of a prophylactic or therapeutic dose of 0281 Flumazenil clonazepam, or one of its Salts, in the acute or chronic management of disease will vary with the Severity of the 0282 Flumazenil is a imidazodiazepine marketed under condition to be treated and the route of administration. The the tradename ROMAZICONGR). Procedures for the prepa dose, and perhaps the dose frequency, will also vary accord ration of flumazenil are described in U.S. Pat. No. 4,316, ing to the age, body weight, and response of the individual patient. In general, the total daily dose ranges, for the 839. The pharmacological properties are described in W. conditions described herein, is from about 1 mg to about 40 Hunkeler et al. Nature 1981, 290, 514; S. E. File et al. mg. Preferably, a daily dose range should be between about Psychopharmacol. 1986, 89, 113; and A. Darragh et al. 2 mg to about 30 mg. Most preferably, a daily dose range Lancet 1981, 2, 8. Flumazenil has the chemical name should be between about 4 mg to about 20 mg. In certain 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo1.5-a1, embodiments, the daily dose range should be about 8, 12, or 4)benzodiazepine-3-carboxylic acid ethyl ester and the 16 mg. In managing the patient, the therapy may be initiated Structure is presented below. US 2005/0176680 A1 Aug. 11, 2005 33

3-12 years old may be given a dose in the range of about 10-15 mg/kg/day up to about 25-35 mg/kg/day. 0287 2-Hydroxysaclofen 0288 2-Hydroxysaclofen is a GABA-receptor antagonist that has the chemical name (RS)-3-amino-2-(4-chlorophe nyl)-2-hydroxypropyl-Sulphonic acid. 2-HydroxySaclofen can be purchased from KOMA Biotech, Inc. The pharma cological properties are described in Kerr et al. NeurOSci. Lett. 1988, 92, 92; Curtis et al. Neurosci. Lett. 1988, 92, 97. 0283 The size of a prophylactic or therapeutic dose of In general, the total daily dose range is from about 1 mg to flumazenil, or one of its Salts, in the acute or chronic about 2000 mg. Preferably, a daily dose range should be management of disease will vary with the Severity of the between about 5 mg to about 1000 mg. More preferably, a condition to be treated and the route of administration. The daily dose range should be between about 10 mg to about dose, and perhaps the dose frequency, will also vary accord 250 mg. The structure of 2-hydroxysaclofen is presented ing to the age, body weight, and response of the individual below. patient. In general, the total daily dose ranges, for the conditions described herein, is from about 0.01 mg to about 4.0 mg. Preferably, a daily dose range should be between C about 0.1 mg to about 2.0 mg. Most preferably, a daily dose range should be between about 0.2 mg to about 1.0 mg. In certain embodiments, the daily dose range should be about 0.4,0.6, or 0.8 mg. In managing the patient, the therapy may be initiated at a lower dose, perhaps about 0.15 mg to about O 0.17 mg and increased up to about 0.5 mg or higher depending on the patient's global response. HN -oil 0284) Gabapentin (NEURONTINGR) OH O 0285) Gabapentin is a GABA-receptor agonist marketed under the tradename NEURONTINCE). Procedures for the 0289 Isoguvacine preparation of gabapentin are described in U.S. Pat. No. 4,024,175. The pharmacological properties are described in 0290) Isoguvacine is a GABA receptor agonist. The phar K. O. Vollmer et al. Arzneimittel-Forsch. 1986, 36,830 and macological properties of isoguvacine are described in Che The US Gabapentin Study Group No. 5 Neurology 1993,43, bib, M.; Johnston, G. A. Clin. Exp. Pharamacol. Physiol. 2292. Gabapentin has the chemical name 1-(aminomethyl 1999, 26, 937-940; X. Leinekugel et al. J. Physiol. 1995, )cyclohexaneacetic acid and the structure is presented 487, 319-29; and White, W. F.; Snodgrass, S. R. J. Neuro below. chem. 1983, 40(6), 1701-8. In general, the total daily dose range is from about 1 mg to about 2000 mg. Preferably, a daily dose range should be between about 5 mg to about 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg. The structure of isoguvacine is presented below. CO2H

0286 The size of a prophylactic or therapeutic dose of gabapentin, or one of its Salts, in the acute or chronic management of disease will vary with the Severity of the condition to be treated and the route of administration. The HN dose, and perhaps the dose frequency, will also vary accord ing to the age, body weight, and response of the individual patient. In general, the total daily dose ranges, for the conditions described herein, is from about 100 mg to about 0291 Lamotrigine (LAMICTAL(R) 3000 mg. Preferably, a daily dose range should be between about 450 mg to about 2400 mg. Most preferably, a daily 0292 Lamotrigine is a GABA-receptor agonist marketed dose range should be between about 900 mg to about 1800 under the tradename LAMICTALE). Procedures for the mg. In certain embodiments, the daily dose range should be preparation of lamotrigine are described in U.S. Pat. No. about 1100, 1300, 1500, or 1700 mg. In managing the 4,602,017 and EP 21,121. The pharmacological properties patient, the therapy may be initiated at a lower dose, perhaps are described in A. F. Cohen et al. Clin. Pharmacol. Ther. about 500 mg to about 700 mg and increased up to about 1987, 42,535; Epilepsia 1991, 32(Supp. 2), S9-S21; and K. 1400 mg or higher depending on the patient's global L. Goa et al. Drugs 1993, 46, 152-157. Lamotrigine has the response. In general, children ages 3-12 years old are given chemical name 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-di a Smaller dosage. For example, a child between the age of amine and the Structure is presented below. US 2005/0176680 A1 Aug. 11, 2005 34

certain embodiments, the daily dose range should be about 2, 3, 4, or 5 mg. In managing the patient, the therapy may C be initiated at a lower dose, perhaps about 0.6 mg to about 0.8 mg and increased up to about 1.5 mg or higher depend Cl ing on the patient's global response. 0297 L-655708 N 0298 L-655708 is a benzodiazepine that binds selec tively to the GABA receptor. L-655708 has the chemical HN es NH2 name 11,12,13,13a-tetrahydro-7-methoxy-9-oxo-9H-imi dazol,5-alpyrrolo2,1-c1,4)benzodiazepine-1-carboxylic acid, ethyl ester. L-655708 can be purchased from KOMA 0293. The size of a prophylactic or therapeutic dose of Biotech, Inc. The pharmacological properties are described lamotrigine, or one of its Salts, in the acute or chronic in Quirk et al. Neuropharmacology 1996, 35, 1331; Sur et al. management of disease will vary with the Severity of the Mol. Pharmacol. 1998, 54,928; and Sur et al. Brain Res. condition to be treated and the route of administration. The 1999, 822, 265. In general, the total daily dose range is from dose, and perhaps the dose frequency, will also vary accord about 1 mg to about 2000 mg. Preferably, a daily dose range ing to the age, body weight, and response of the individual should be between about 5 mg to about 1000 mg. More patient. In general, the total daily dose ranges, for the preferably, a daily dose range should be between about 10 conditions described herein, is from about 5 mg to about mg to about 250 mg. The structure of L-655708 is presented 1000 mg. Preferably, a daily dose range should be between below. about 25 mg to about 750 mg. Most preferably, a daily dose range should be between about 50 mg to about 500 mg. In certain embodiments, the daily dose range should be about 100, 200, 300 or 400 mg. In managing the patient, the therapy may be initiated at a lower dose, perhaps about 40 mg to about 75 mg and increased up to about 250 mg or higher depending on the patient's global response. 0294 Lorazepam 0295) Lorazepam is an antianxiety agent marketed under the tradename ATIVANCR). Procedures for the preparation of lorazepam are described in U.S. Pat. No. 3,296,249. The pharmacological properties are described in Arzneimittel Forsch. 1971, 21, 1047-1102 and Ameer, B., Greenblatt, D. 0299 Midazolam J. Drugs 1981, 21, 161-200. Lorazepam has the chemical name 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy 0300 Midazolam is a short-acting derivative of diaz 2H-1,4-benzodiazepin-2-one and the Structure is presented epam. Procedures for the preparation of midazolam are below. described in U.S. Pat. No. 4,280,957. The pharmacological properties are described in Brit. J. Clin. Pharmacol. 1983, 16 (Suppl. 1), IS-199S; J. W. Dundee et al. Drugs 1984, 28, 519-543; and E. Lahat et al. Brit. Med. J. 2000, 321, 83. Midazolam has the chemical name 8-chloro-6-(2-fluorophe nyl)-1-methyl-4H-imidazol,5-a1,4)benzodiazepine and OH the Structure is presented below. Cl O

0296. The size of a prophylactic or therapeutic dose of lorazepam, or one of its Salts, in the acute or chronic management of disease will vary with the Severity of the condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary accord ing to the age, body weight, and response of the individual patient. In general, the total daily dose ranges, for the conditions described herein, is from about 0.1 mg to about 0301 The size of a prophylactic or therapeutic dose of 20 mg. Preferably, a daily dose range should be between midazolam, or one of its Salts, in the acute or chronic about 0.5 mg to about 13 mg. Most preferably, a daily dose management of disease will vary with the Severity of the range should be between about 1 mg to about 6 mg. In condition to be treated and the route of administration. The US 2005/0176680 A1 Aug. 11, 2005 35 dose, and perhaps the dose frequency, will also vary accord Philip et al. Anal. Profiles Drug Subs. 1984, 13, 417–445. In ing to the age, body weight, and response of the individual certain instances, the Sodium Salt of phenytoin is preferred. patient. In general, the total daily dose ranges, for the Phenytoin has the chemical name 5,5-diphenyl-2,4-imida conditions described herein, is from about 0.5 mg to about Zolidinedione and the Structure is presented below. 100 mg. Preferably, a daily dose range should be between about 1 mg to about 40 mg. Most preferably, a daily dose range should be between about 4 mg to about 20 mg. In certain embodiments, the daily dose range should be about 8, 12, or 16 mg. In managing the patient, the therapy may be initiated at a lower dose, perhaps about 2 mg to about 3 mg and increased up to about 6 mg or higher depending on the patient's global response. 0302 Muscimol 0303 Muscimol is a GABA-receptor agonist that has the chemical name 5-(aminomethyl)-3(2H)-isoxazolone. Proce dures for the preparation of muscimol are described in 0308 The size of a prophylactic or therapeutic dose of Nakamura Chem. Pharm. Bull. 1971, 19, 46 and McCarry, phenytoin, or one of its Salts, in the acute or chronic B. E.; Savard, M. Tetrahedron Letters 1981, 22, 5153. The management of disease will vary with the Severity of the pharmacological properties are described in Theobald et al. condition to be treated and the route of administration. The Arzneimittel-Forsch. 1968, 18, 311 and F. V. DeFeudis dose, and perhaps the dose frequency, will also vary accord Neurochem. Res. 1980, 5, 1047-1068. For additional infor ing to the age, body weight, and response of the individual mation see U.S. Pat. Nos. 3,242,190 and 3,397.209. In patient. In general, the total daily dose ranges, for the general, the total daily dose range is from about 1 mg to conditions described herein, is from about 5 mg to about 600 about 2000 mg. Preferably, a daily dose range should be mg. Preferably, a daily dose range should be between about between about 5 mg to about 1000 mg. More preferably, a 15 mg to about 450 mg. Most preferably, a daily dose range daily dose range should be between about 10 mg to about should be between about 25 mg to about 300 mg. In certain 250 mg. The structure of muscimol is presented below. embodiments, the daily dose range should be about 50, 100, 150, 200, or 250 mg. In managing the patient, the therapy may be initiated at a lower dose, perhaps about 10 mg to about 20 mg and increased up to about 75 mg or higher depending on the patient's global response. 0309 Pregabalin 0310 Pregabalin is an isobutyl analog of GABA devel oped by Pfizer in collaboration with researchers at North western University. Pregabalin has a more linear relation 0304 Phaclofen ship between drug plasma levels and the dosage of the drug 0305 Phaclofen is a GABA-receptor antagonist that has compared to gabapentin. Procedures for the preparation of the chemical name 3-amino-2-(4-chlorophenyl)propylphos pregabalin are described in M. J. Burk et al. J. Org. Chem. phonic acid. Phaclofen can be purchased from KOMA 2003, 68, 5731-5734. The pharmacological properties are Biotech, Inc. The pharmacological properties are described described in Bayes, M.; Rabasseda, X.; Prous, J. R. Methods in Kerr et al. Brain Res. 1987, 405, 150; Karlsson et al. Eur: Find Exp. Clin. Pharmacol. 2004, 26(3), 211-44 and A. C. J. Pharmacol. 1988, 148, 485; and Hasuo, Gallagher Neu Pande et al. J. Clin. Psychopharmacol. 2004, 24(2), 141-9. rosci. Lett. 1988, 86, 77. In general, the total daily dose For additional information see U.S. Pat. No. 6,028,214. range is from about 1 mg to about 2000 mg. Preferably, a Pregabalin has the chemical name (S)-(+)-3-aminomethyl daily dose range should be between about 5 mg to about 5-methylhexanoic acid and the Structure is presented below. 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg. The structure of phaclofen is presented below. NH CO2H

0306 Phenytoin (DILANTINGR) 0311. The size of a prophylactic or therapeutic dose of 0307 Phenytoin is a GABA-receptor agonist marketed pregabalin, or one of its Salts, in the acute or chronic under the tradename DILANTINCE). Procedures for the management of disease will vary with the Severity of the preparation of phenytoin are described in U.S. Pat. No. condition to be treated and the route of administration. The 2,409,754. The pharmacological properties are described in dose, and perhaps the dose frequency, will also vary accord Gillis et al. J. Pharmacol. Exp. Ther: 1971, 179, 599 and J. ing to the age, body weight, and response of the individual US 2005/0176680 A1 Aug. 11, 2005 36 patient. In general, the total daily dose ranges, for the conditions described herein, is from about 5 mg to about 1200 mg. Preferably, a daily dose range should be between S about 30 mg to about 800 mg. Most preferably, a daily dose FC X- NH2 range should be between about 75 mg to about 600 mg. In N certain embodiments, the daily dose range should be about 100, 150, 250, 400, or 500 mg. In managing the patient, the therapy may be initiated at a lower dose, perhaps about 50 0317. The size of a prophylactic or therapeutic dose of mg to about 65 mg and increased up to about 125 mg or riluzole, or one of its Salts, in the acute or chronic manage higher depending on the patient's global response. ment of disease will vary with the severity of the condition to be treated and the route of administration. The dose, and 0312 Progabide (GABRENE(R) perhaps the dose frequency, will also vary according to the 0313 Progabide is a GABA receptor antagonist marketed age, body weight, and response of the individual patient. In under the tradename GABRENE(E). Procedures for the general, the total daily dose ranges, for the conditions preparation of progabide are described in U.S. Pat. No. described herein, is from about 5 mg to about 250 mg. Preferably, a daily dose range should be between about 50 4,094,992. The pharmacological properties are described in mg to about 175 mg. Most preferably, a daily dose range I. Johno et al. J. Pharm. Sci. 1982, 71, 633 and U.S. Pat. No. should be between about 80 mg to about 120 mg. In certain 4,361,583. Progabide has the chemical name 4-(4-chlo embodiments, the daily dose range should be about 90, 100, rophenyl)-(5-fluoro-2-hydroxyphenyl)methylenelamino or 110 mg. In managing the patient, the therapy may be butanamide and the Structure is presented below. initiated at a lower dose, perhaps about 60 mg to about 70 mg and increased up to about 100 mg or higher depending on the patient's global response. NH2 OH r-r 0318 Saclofen O 0319 Saclofen is a GABA-receptor antagonist that has the chemical name (RS)-3-amino-2-(4-chlorophenyl)pro pylsulphonic acid. Saclofen can be purchased from KOMA Cl Biotech, Inc. The pharmacological properties are described in Bowery TiPS. 1989, 10, 401; Kerr et al. Neurosci. Lett. 1989, 107, 239; and Jane et al. in GABA Receptors in Mammalian Function. Eds. Bowery et al., p. 42b, John Wiley 0314. The size of a prophylactic or therapeutic dose of & Sons, 1990, Chichester, U. K. In general, the total daily progabide, or one of its Salts, in the acute or chronic dose range is from about 1 mg to about 2000 mg. Preferably, management of disease will vary with the Severity of the a daily dose range should be between about 5 mg to about condition to be treated and the route of administration. The 1000 mg. More preferably, a daily dose range should be dose, and perhaps the dose frequency, will also vary accord between about 10 mg to about 250 mg. The structure of ing to the age, body weight, and response of the individual Saclofen is presented below. patient. In general, the total daily dose ranges, for the conditions described herein, is from about 5 mg/kg/day to C about 75 mg/kg/day. Preferably, a daily dose range should be between about 15 mg/kg/day to about 55 mg/kg/day. Most preferably, a daily dose range should be between about 25 mg/kg/day to about 45 mg/kg/day. In certain embodiments, the daily dose range should be about about 30, 35, or 40 mg/kg/day. In managing the patient, the therapy may be HN S-OH initiated at a lower dose, perhaps about 10 mg/kg/day to about 15 mg/kg/day and increased up to about 30 mg/kg/day or higher depending on the patient's global response. 0315) Riluzole 0320 SCH50911 0321 SCH 50911 is a GABA-receptor antagonist that has 0316 Riluzole is a benzothiazole derivative marketed by the chemical name (2S)-5,5-dimethyl-2-morpholineacetic Rhone Poulenc Rorer. Procedures for the preparation of acid. SCH 50911 can be purchased from KOMA Biotech, riluzole are described in U.S. Pat. No. 4,370,338 and EP Inc. The pharmacological properties are described in Bolser 50,551. The pharmacological properties are described in J. et al. J. Pharmacol. Exp. Ther. 1996, 274, 1393; Hosford et Mizoule et al. Neuropharmacology 1985, 24, 767 amd M. al. J. Pharmacol. Exp. Ther: 1996, 274, 1399; and Ong et al. W. Debono et al. Eur: J Pharmacol. 1993, 235, 283. Riluzole Eur: J. Pharmacol. 1998, 362,35. In general, the total daily has the chemical name 6-(trifluoromethoxy)benzothiaz dose range is from about 1 mg to about 2000 mg. Preferably, olamine and the Structure is presented below. a daily dose range should be between about 5 mg to about US 2005/0176680 A1 Aug. 11, 2005 37

1000 mg. More preferably, a daily dose range should be 0326 Tiagabine (GABITIRIL(R) between about 10 mg to about 250 mg. The structure of SCH 0327. Tiagabine is a GABA uptake inhibitor marketed 50911 is presented below. under the tradename GABITIRILE). Procedures for the preparation of tiagabine are described in U.S. Pat. No. 5,010,090 and K. E. Andersen et al. J. Med. Chem. 1993, 36, 1716. The pharmacological properties are described in C. L. Faingold et al. Exp. Neurology 1994, 126, 225 and W. J. Giardina J. Epilepsy 1994, 7, 161-166. Tiagabine has the chemical name (R)-1-4.4-bis(3-methyl-2-thienyl)-3-bute nyl-3-piperidinecarboxylic acid and the structure is pre sented below. 0322. SKF 97541

0323 SKF 97541 is a GABA-receptor agonist with the chemical name 3-aminopropyl(methyl)phosphinic acid. SKF97541 is a white solid that is readily soluble in Sater and dilute aqueous base. SKF 97541 can be purchased from A.G. Scientific, Inc. located in San Diego, Calif. The pharmaco CO2H logical properties are described in Hoskison, M. M.; Connor, J. A.; Shuttleworth, C. W. Neurosci. Lett. 2004, 365(1), 48-53 and Hue, B.; Amat, C.J Insect Physiol. 1997, 43(12), 1125-1131. In certain instances, the hydrochloride salt is preferred. In general, the total daily dose range is from about 0328. The size of a prophylactic or therapeutic dose of 1 mg to about 2000 mg. Preferably, a daily dose range tiagabine, or one of its Salts, in the acute or chronic man should be between about 5 mg to about 1000 mg. More agement of disease will vary with the severity of the preferably, a daily dose range should be between about 10 condition to be treated and the route of administration. The mg to about 250 mg. The structure of SKF 97541 is dose, and perhaps the dose frequency, will also vary accord presented below. ing to the age, body weight, and response of the individual patient. In general, the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 100 O mg. Preferably, a daily dose range should be between about 15 mg to about 50 mg. Most preferably, a daily dose range 2NN-11 P should be between about 30 mg to about 35 mg. In certain YoH embodiments, the daily dose range should be about 32 or 34 mg. In managing the patient, the therapy may be initiated at a lower dose, perhaps about 5 mg to about 10 mg and increased up to about 20 mg or higher depending on the 0324) SR 95531 patient's global response. 0325 SR 95531 is a GABA-receptor antagonist. SR 95531 can be purchased from Tocris Cookson Inc. in Ellis 0329) TPMPA Ville, Mo. The pharmacological properties are described in 0330 TPMPA is a GABA-receptor antagonist. TPMPA B. M. Stell et al. J. Neurosci. 2002, 22(10), RC223. In can be purchased from Tocris Cookson Inc. in Ellisville, Mo. general, the total daily dose range is from about 1 mg to The pharmacological properties of TPMPA are described in about 2000 mg. Preferably, a daily dose range should be K. Schlicker et al. Brain Res. Bull. 2004, 63(2), 91-7. In between about 5 mg to about 1000 mg. More preferably, a general, the total daily dose range is from about 1 mg to daily dose range should be between about 10 mg to about about 2000 mg. Preferably, a daily dose range should be 250 mg. The structure of SR 95531 is presented below. between about 5 mg to about 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg. The Structure of isoguvacine is presented below. NH r-r OH 2 N O

HN

0331) Topiramate (TOPAMAX(R) ON 0332 Topiramate is a fructopyranose derivative mar keted under the tradename TOPAMAX(R). Procedures for the preparation of topiramate are described in U.S. Pat. No. US 2005/0176680 A1 Aug. 11, 2005 38

4.513,006. The pharmacological properties are described in embodiments, the daily dose range should be about 100, M. Bialer Clin. Pharmacokinet. 1993, 24, 441 and B. E. 200, 300 or 400 mg. In managing the patient, the therapy Maryanoff et al J. Med. Chem. 1987, 30,880. Topiramate may be initiated at a lower dose, perhaps about 20 mg to has the chemical name 2,3:4,5-bis-O-(1-methylethylidene)- about 40 mg and increased up to about 75 mg or higher f3-D-fructopyranose Sulfamate and the structure is presented depending on the patient’s global response. below. 0337 Vigabatrin

0338 Vigabatrin has the chemical name 4-amino-5-hex enoic acid and is used to prevent seizures in people suffering from epilepsy. Procedures for the preparation of vigabatrin are described in U.S. Pat. No. 3,960,927. The pharmaco logical properties are described in K. D. Haegele et al. Clin. Pharmacol. Ther: 1986, 40, 581 and Grant, S. M.; Heel, R. C. Drugs 1991, 41, 889-926. The structure of vigabatrin is presented below. 0333) The size of a prophylactic or therapeutic dose of topiramate, or one of its salts, in the acute or chronic management of disease will vary with the severity of the --~ COH condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary accord ing to the age, body weight, and response of the individual patient. In general, the total daily dose ranges, for the 0339) The size of a prophylactic or therapeutic dose of conditions described herein, is from about 5 mg to about 400 Vigabatrin, or one of its salts, in the acute or chronic mg. Preferably, a daily dose range should be between about management of disease will vary with the severity of the 100 mg to about 300 mg. Most preferably, a daily dose range condition to be treated and the route of administration. The should be between about 170 mg to about 230 mg. In certain dose, and perhaps the dose frequency, will also vary accord embodiments, the daily dose range should be about 180, ing to the age, body weight, and response of the individual 190, 200, 210, or 220 mg. In managing the patient, the patient. In general, the total daily dose ranges, for the therapy may be initiated at a lower dose, perhaps about 125 conditions described herein, is from about 100 mg to about mg to about 150 mg and increased up to about 175 mg or 5000 mg. Preferably, a daily dose range should be between higher depending on the patient’s global response. In gen about 500 mg to about 4000 mg. Most preferably, a daily eral, children a given a Smaller dosage. dose range should be between about 1000 mg to about 3000 mg. In certain embodiments, the daily dose range should be 0334) Valproic Acid about 1200, 1500, 2000, or 2500 mg. In managing the 0335) Valproic acid has the chemical name 2-propylpen patient, the therapy may be initiated at a lower dose, perhaps tanoic acid and is used to treat migraine headaches and about 700 mg to about 900 mg and increased up to about prevent Seizures in people Suffering from epilepsy. Proce 1300 mg or higher depending on the patient's global dures for the preparation of valproic acid are described in response. Weimann, Thuan Bull. Soc. Chim. France 1958, 199. The pharmacological properties are described in Rimmer, E. M.; 0340 Additional GABA receptor modulating compounds Richens, A. Pharmacother. 1985, 5, 171-184 and Z. L. amenable to the present invention include the GABA recep Chang in Analytical Profiles of Drug Substances vol. 8, K. tor agonists described in U.S. patent application 20030162754 and WO 02/06786, which are hereby incor Florey, Ed. (Academic Press, New York, 1979) pp 529-556. porated by reference. For example, compounds amenable to The structure of valproic acid is presented below. the present invention include 4-amino-3-phenylbutanoic acid, 4-amino-3-hydroxybutanoic acid, 4-amino-3-(4-chlo rophenyl)-3-hydroxyphenylbutanoic acid, 4-amino-3- (thien-2-yl)butanoic acid, 4-amino-3-(5-chlorothien-2- yl)butanoic acid, 4-amino-3-(5-bromothien-2-yl)butanoic acid, 4-amino-3-(5-methylthien-2-yl)butanoic acid, CO2H 4-amino-3-(2-imidazolyl)butanoic acid, 4-guanidino-3-(4- chlorophenyl)butanoic acid, 3-amino-2-(4-chlorophenyl)-1- 0336) The size of a prophylactic or therapeutic dose of nitropropane, (3-aminopropyl)phosphonous acid, (4-ami Valproic acid, or one of its Salts, in the acute or chronic nobut-2-yl)phosphonous acid, (3-amino-2- management of disease will vary with the severity of the methylpropyl)phosphonous acid, condition to be treated and the route of administration. The (3-aminobutyl)phosphonous acid, (3-amino-2-(4-chlorophe dose, and perhaps the dose frequency, will also vary accord nyl)propyl)phosphonous acid, (3-amino-2-(4-chlorophe ing to the age, body weight, and response of the individual nyl)-2-hydroxypropyl)phosphonous acid, (3-amino-2-(4- patient. In general, the total daily dose ranges, for the fluorophenyl)propyl)phosphonous acid, (3-amino-2- conditions described herein, is from about 5 mg to about 900 phenylpropyl)phosphonous acid, (3-amino-2- mg. Preferably, a daily dose range should be between about hydroxypropyl)phosphonous acid, (E)-(3-aminopropen-1- 25 mg to about 700 mg. Most preferably, a daily dose range yl)phosphonous acid, (3-amino-2- should be between about 50 mg to about 500 mg. In certain cyclohexylpropyl)phosphonous acid, (3-amino-2-

US 2005/0176680 A1 Aug. 11, 2005

pyridazine; 6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3- certain embodiments, the first and Second therapeutic agents (2-fluorophenyl)-7-(thiophen-3-yl)1,2,4-triazolo 4,3-b are administered in a Single dosage form. The agents may be pyridazine; 3-(2-fluorophenyl)-7-(1-methylcyclobutyl)-6- formulated into a single tablet, pill, capsule, or Solution for (2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo.4, parenteral administration and the like. 3-bipyridazine; 3-(2-fluorophenyl)-7-(1-methylcyclobutyl)- 6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo 0347 Alternatively, the first therapeutic agent and the 4,3-bpyridazine; 6-(1-methyl-1H-1,2,4-triazol-3- Second therapeutic agents may be administered as Separate ylmethoxy)-3(2-fluorophenyl)-7-(thiophen-3-yl)-1,2,4- compositions, e.g., as Separate tablets or Solutions. The first triazolo 4,3-bipyridazine; 8-methyl-7-(1- active agent may be administered at the same time as the methylcyclobutyl)-6-(1-methyl-1H-1,2,4-triazol-3- Second active agent or the first active agent may be admin ylmethoxy)-3-phenyl-1,2,4-triazolo 4,3-bipyridazine; istered intermittently with the Second active agent. The 8-methyl-7-(1-methylcyclobutyl)-6-(2-methyl-2H-1,2,4- length of time between administration of the first and Second triazol-3-ylmethoxy)-3-phenyl-1,2,4-triazolo 4,3-bpy therapeutic agent may be adjusted to achieve the desired ridazine; 6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3-phe therapeutic effect. In certain instances, the Second therapeu nyl-7-(pyrrolidin-1-yl)-1,2,4-triazolo 4,3-bpyridazine; tic agent may be administered only a few minutes (e.g., 1, 2, 7-cyclobutyl-8-methyl-6-(2-methyl-2H-1,2,4-triazol-3-yl 5, 10, 30, or 60 min) after administration of the first methoxy)-3-phenyl-1,2,4-triazolo.4,3-bpyridazine; 7-cy therapeutic agent. Alternatively, the Second therapeutic clobutyl-8-methyl-6-(1-methyl-1H-1,2,4-triazol-3-yl agent may be administered several hours (e.g., 2, 4, 6, 10, 12, 24, or 36 hr) after administration of the first therapeutic methoxy)-3-phenyl-1,2,4-triazolo.4,3-bpyridazine; 7-(1- agent. In certain embodiments, it may be advantageous to methylcyclopentyl)-6-(2-methyl-2H-1,2,4-triazol-3- administer more than one dosage of the Second therapeutic ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo 4,3-b agent between administrations of the first therapeutic agent. pyridazine; and 7-(1-methylcyclopentyl)-6-(1-methyl 1H-1, For example, the Second therapeutic agent may be admin 2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo istered at 2 hours and then again at 10 hours following 4,3-bpyridazine. administration of the first therapeutic agent. Alternatively, it 0342 Additional GABA modulating agents for use in the may be advantageous to administer more than one dosage of present invention are 3-amino-propyl phosphinic acid and the first therapeutic agent between administrations of the (1S,2R)-(+)-2-(aminomethyl)-cyclopropane-1-carboxylate. Second therapeutic agent. Importantly, it is preferred that the The Structure of 3-amino-propyl phosphinic acid is pre therapeutic effects of each active ingredient overlap for at sented below. least a portion of the duration of each therapeutic agent So that the overall therapeutic effect of the combination therapy is attributable in part to the combined or Synergistic effects O of the combination therapy. HN P 0348 The dosage of the active agents will generally be 2 N1 a-1\ot dependent upon a number of factors including pharmaco H dynamic characteristics of each agent of the combination, mode and route of administration of active agent(s), the health of the patient being treated, the extent of treatment 0343 The structure of (1S,2R)-(+)-2-(aminomethyl)-cy desired, the nature and kind of concurrent therapy, if any, clopropane-1-carboxylate is presented below. and the frequency of treatment and the nature of the effect desired. In general, dosage ranges of the active agents often range from about 0.001 to about 250 mg/kg body weight per day. For example, for a normal adult having a body weight of about 70 kg, a dosage in the range of from about 0.1 to about 25 mg/kg body weight is typically preferred. How ever, Some variability in this general dosage range may be required depending upon the age and weight of the Subject being treated, the intended route of administration, the 0344 Combination Therapy particular agent being administered and the like. Since two or more different active agents are being used together in a 0345 One aspect of the present invention relates to combination therapy, the potency of each agent and the combination therapy. This type of therapy is advantageous interactive effects achieved using them together must be because the co-administration of active ingredients achieves considered. Importantly, the determination of dosage ranges a therapeutic effect that is greater than the therapeutic effect and optimal dosages for a particular mammal is also well achieved by administration of only a single therapeutic within the ability of one of ordinary skill in the art having the agent. In one embodiment, the co-administration of two or benefit of the instant disclosure. more therapeutic agents achieves a Synergistic effect, i.e., a therapeutic affect that is greater than the Sum of the thera 0349. In certain embodiments, it may be advantageous peutic effects of the individual components of the combi for the pharmaceutical combination to have a relatively large nation. In another embodiment, the co-administration of two amount of the first component compared to the Second or more therapeutic agents achieves an augmentation effect. component. In certain instances, the ratio of the first active agent to second active agent is 30:1, 20:1, 15:1, 10:1, 9:1, 0346) The active ingredients that comprise a combination 8:1, 7:1, 6:1, or 5:1. In certain embodiments, it may be therapy may be administered together via a single dosage preferable to have a more equal distribution of pharmaceu form or by Separate administration of each active agent. In tical agents. In certain instances, the ratio of the first active US 2005/0176680 A1 Aug. 11, 2005 42 agent to the Second active agent is 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, cedures in cell cultures or experimental animals, e.g., for or 1:4. In certain embodiments, it may be advantageous for determining the LDs (the dose lethal to 50% of the popu the pharmaceutical combination to have a relatively large lation) and the EDso (the dose therapeutically effective in amount of the Second component compared to the first 50% of the population). The dose ratio between toxic and component. In certain instances, the ratio of the Second therapeutic effects is the therapeutic indeX and it can be active agent to the first active agent is 30:1, 20:1, 15:1, 10:1, expressed as the ratio LDs/EDs. Compounds which 9:1, 8:1, 7:1, 6:1, or 5:1. Importantly, a composition com exhibit large therapeutic indices are preferred. The data prising any of the above-identified combinations of first obtained from these cell culture assays and animal Studies therapeutic agent and Second therapeutic agent may be can be used in formulating a range of dosage for use in administered in divided doses 1, 2, 3, 4, 5, 6, or more times humans. The dosage of Such compounds lies preferably per day or in a form that will provide a rate of release within a range of circulating concentrations that include the effective to attain the desired results. In a preferred embodi EDso with little or no toxicity. The dosage may vary within ment, the dosage form contains both the first and Second this range depending upon the dosage form employed and active agents. In a more preferred embodiment, the dosage the route of administration utilized. For any compound used form only has to be administered one time per day and the in the method of the invention, the therapeutically effective dosage form contains both the first and Second active agents. dose can be estimated initially from cell culture assays. A 0350 For example, a formulation intended for oral dose may be formulated in animal models to achieve a administration to humans may contain from 0.1 mg to 5g of circulating plasma concentration range that includes the ICso the first therapeutic agent and 0.1 mg to 5 g of the Second (i.e., the concentration of the test compound which achieves therapeutic agent, both of which are compounded with an a half-maximal inhibition of RT production from infected appropriate and convenient amount of carrier material vary cells compared to untreated control as determined in cell ing from about 5 to about 95 percent of the total composi culture. Such information can be used to more accurately tion. Unit dosages will generally contain between from determine useful doses in humans. Levels in plasma may be about 0.5 mg to about 1500 mg of the first therapeutic agent measured, for example, by high performance liquid chro and 0.5 mg to about 1500 mg of the second therapeutic matography (HPLC). agent. In a preferred embodiment, the dosage comprises 0.5 0353 Synergism and Augmentation mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg,300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 0354) The term “synergistic” refers to a combination or 1000 mg, etc., up to 1500 mg of the first therapeutic agent. which is more effective than the additive effects of any two In a preferred embodiment, the dosage comprises 0.5 mg, 1 or more Single agents. A Synergistic effect permits the mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, effective treatment of a disease using lower amounts (doses) 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 of either individual therapy. The lower doses result in lower mg, etc., up to 1500 mg of the Second therapeutic agent. toxicity without reduced efficacy. In addition, a Synergistic effect can result in improved efficacy, e.g., improved anti 0351. The optimal ratios of the first and second thera Viral activity. Finally, Synergy may result in an improved peutic agent can be determined by Standard assays known in avoidance or reduction of disease as compared to any Single the art. For example, the phenyl-p-benzoquinone test may be therapy. used to establish analgesic effectiveness. The phenyl-p- benzoquinone induced writhing test in mice (H. Blumberget 0355 Combination therapy can allow for the use of lower al., 1965, Proc. Soc. Exp. Med. 118:763-766) and known doses of the first therapeutic or the Second therapeutic agent modifications thereof is a Standard procedure which may be (referred to as “apparent one-way Synergy' herein), or lower used for detecting and comparing the analgesic activity of doses F both therapeutic agents (referred to as “two-way different classes of analgesic drugs with a good correlation Synergy herein) than would normally be required when with human analgesic activity. Data for the mouse, as either drug is used alone. presented in an isobologram, can be translated to other 0356. In certain embodiments, the synergism exhibited Species where the orally effective analgesic dose of the between the Second therapeutic agent and the first therapeu individual compounds are known or can be estimated. The tic agent is Such that the dosage of the first therapeutic agent method consists of reading the percent EDso dose for each would be Sub-therapeutic if administered without the dosage dose ratio on the best fit regression analysis curve from the of the Second therapeutic agent. Alternatively, the Synergism mouse isobologram, multiplying each component by its exhibited between the Second therapeutic agent and the first effective species dose, and then forming the ratio of the therapeutic agent is Such that the dosage of the Second amount of COX-2 inhibitor and opioid analgesic. This basic therapeutic agent would be Sub-therapeutic if administered correlation for analgesic properties enables estimation of the without the dosage of the first therapeutic agent. range of human effectiveness (E. W. Pelikan, 1959, The Pharmacologist 1:73). Thus, application of an equieffective 0357 The terms “augmentation” or “augment” refer to dose Substitution model and a curvilinear regression analysis combination where one of the compounds increases or utilizing all the data for the individual compounds and enhances therapeutic effects of another compound or com various dose ratioS for the combinations can be used to pounds administered to a patient. In Some instances, aug establish the existence of unexpectedly enhanced analgesic mentation can result in improving the efficacy, tolerability, activity of combinations of active agents, i.e., the resulting or Safety, or any combination thereof, of a particular therapy. activity is greater than the activity expected from the Sum of 0358 In certain embodiments, the present invention the activities of the individual components. relates to a pharmaceutical composition comprising a thera 0352. The toxicity and therapeutic efficacy of such com peutically effective dose of a first therapeutic agent together pounds can be determined by Standard pharmaceutical pro with a dose of a Second therapeutic agent effective to US 2005/0176680 A1 Aug. 11, 2005 43 augment the therapeutic effect of the first therapeutic agent. of the widely accepted method of Chou and Talalay com In other embodiments, the present invention relates to meth bined with a statistically evaluation using the Monte Carlo ods of augmenting the therapeutic effect in a patient of a first Statistical package. The data are displayed in Several differ therapeutic agent by administering the Second therapeutic ent formats including median-effect and dose-effects plots, agent to the patient. In other embodiments, the present isobolograms, and combination index CI plots with stan invention relates to a pharmaceutical composition compris dard deviations. For the latter analysis, a CI greater than 1.0 ing an therapeutically effective dose of a Second therapeutic indicates antagonism and a CI leSS than 1.0 indicates Syn agent together with a dose of a first therapeutic agent ergism. effective to augment the therapeutic effect of the Second 0362 Compositions of the invention present the oppor therapeutic agent. In other embodiments, the present inven tunity for obtaining relief from moderate to Severe cases of tion relates to methods of augmenting the therapeutic effect disease. Due to the Synergistic and/or additive effects pro in a patient of a Second therapeutic agent by administering vided by the inventive combination of the first and second the first therapeutic agent to the patient. therapeutic agent, it may be possible to use reduced dosages 0359. In certain preferred embodiments, the invention is of each of therapeutic agent. By using lesser amounts of directed in part to Synergistic combinations of the first other or both drugs, the Side effects associated with each therapeutic agent in an amount Sufficient to render a thera may be reduced in number and degree. Moreover, the peutic effect together with a Second therapeutic agent. For inventive combination avoids side effects to which some example, in certain embodiments a therapeutic effect is patients are particularly Sensitive. attained which is at least about 2 (or at least about 4, 6, 8, 0363 Compositions & Methods of the Invention or 10) times greater than that obtained with the dose of the first therapeutic agent alone. In certain embodiments, the 0364 One aspect of the present invention relates to a Synergistic combination provides a therapeutic effect which pharmaceutical composition comprising eSZopiclone, or a is up to about 20, 30 or 40 times greater than that obtained pharmaceutically acceptable Salt, Solvate, clathrate, poly with the dose of first therapeutic agent alone. In Such morph, or co-crystal thereof, and a Serotonin reuptake embodiments, the Synergistic combinations display what is inhibitor. referred to herein as an "apparent one-way Synergy', mean 0365 Another aspect of the present invention relates to a ing that the dose of Second therapeutic agent Synergistically pharmaceutical composition comprising eSZopiclone, or a potentiates the effect of the first therapeutic agent, but the pharmaceutically acceptable Salt, Solvate, clathrate, poly dose of first therapeutic agent does not appear to Signifi morph, or co-crystal thereof, and a serotonin reuptake cantly potentiate the effect of the Second therapeutic agent. inhibitor, wherein Said Serotonin reuptake inhibitor is cit 0360. In certain embodiments, the combination of active allopram, dulloxetine, escitalopram, fluoxetine, fluvoxamine, agents exhibit two-way Synergism, meaning that the Second milnacipran, paroxetine, Sertraline, clominpramine, femox therapeutic agent potentiates the effect of the first therapeu etine, indapline, alaprolclate, cericlamine, or ifoxetine, or a tic agent, and the first therapeutic agent potentiates the effect pharmaceutically acceptable Salt, Solvate, clathrate, poly of the Second therapeutic agent. Thus, other embodiments of morph, or co-crystal of any one of them. the invention relate to combinations of a Second therapeutic 0366. In certain embodiments, the present invention agent and a first therapeutic agent where the dose of each relates to the aforementioned pharmaceutical composition, drug is reduced due to the Synergism between the drugs, and wherein Said Serotonin reuptake inhibitor is fluoxetine, flu the therapeutic effect derived from the combination of drugs VOXamine, milnacipran, or paroxetine, or a pharmaceutically in reduced doses is enhanced. The two-way Synergism is not acceptable Salt, Solvate,...clathrate, polymorph, or co-crystal always readily apparent in actual dosages due to the potency of any one of them. ratio of the first therapeutic agent to the Second therapeutic 0367. In certain embodiments, the present invention agent. For instance, two-way Synergism can be difficult to relates to the aforementioned pharmaceutical composition, detect when one therapeutic agent displays much greater wherein Said Serotonin reuptake inhibitor is fluoxetine, par therapeutic potency relative to the other therapeutic agent. oxetine, or a pharmaceutically acceptable Salt, Solvate, clath 0361 The synergistic effects of combination therapy may rate, polymorph, or co-crystal of either of them. be evaluated by biological activity assayS. For example, the 0368. In certain embodiments, the present invention therapeutic agents are be mixed at molar ratioS designed to relates to the aforementioned pharmaceutical composition, give approximately equipotent therapeutic effects based on wherein Said Serotonin reuptake inhibitor is fluoxetine, or a the ECo values. Then, three different molar ratios are used pharmaceutically acceptable Salt, Solvate, clathrate, poly for each combination to allow for variability in the estimates morph, or co-crystal thereof. of relative potency. These molar ratios are maintained throughout the dilution Series. The corresponding mono 0369. In certain embodiments, the present invention therapies are also evaluated in parallel to the combination relates to the aforementioned pharmaceutical composition, treatments using the Standard primary assay format. A com wherein Said fluoxetine is fluoxetine hydrochloride, or a parison of the therapeutic effect of the combination treat pharmaceutically acceptable Solvate, clathrate, polymorph, ment to the therapeutic effect of the monotherapy gives a or co-crystal thereof. measure of the Synergistic effect. Further details on the 0370 Another aspect of the present invention relates to a design of combination analyses can be found in B E Korba pharmaceutical composition consisting essentially of (1996) Antiviral Res. 29:49. Analysis of synergism, addi eSZopiclone, or a pharmaceutically acceptable Salt, Solvate, tivity, or antagonism can be determined by analysis of the clathrate, polymorph, or co-crystal thereof; a Serotonin aforementioned data using the CalcuSynTM program (Bio reuptake inhibitor; and at least one pharmaceutically accept Soft, Inc.). This program evaluates drug interactions by use able carrier. US 2005/0176680 A1 Aug. 11, 2005 44

0371 Another aspect of the present invention relates to a nin reuptake inhibitor is fluoxetine, paroxetine, or a phar pharmaceutical composition consisting essentially of maceutically acceptable Salt, Solvate, clathrate, polymorph, eSZopiclone, or a pharmaceutically acceptable Salt, Solvate, or co-crystal of either of them. clathrate, polymorph, or co-crystal thereof; a Serotonin reuptake inhibitor, wherein Said Serotonin reuptake inhibitor 0380. In certain embodiments, the present invention is citalopram, dulloxetine, escitalopram, fluoxetine, fluvox relates to the aforementioned method, wherein Said Seroto amine, milnacipran, paroxetine, Sertraline, clominpramine, nin reuptake inhibitor is fluoxetine, or a pharmaceutically femoxetine, indapline, alaprolclate, cericlamine, or ifoxet acceptable Salt, Solvate, clathrate, polymorph, or co-crystal ine, or a pharmaceutically acceptable Salt, Solvate, clathrate, thereof. polymorph, or co-crystal of any one of them; and at least one 0381. In certain embodiments, the present invention pharmaceutically acceptable carrier. relates to the aforementioned method, wherein Said fluox etine is fluoxetine hydrochloride, or a pharmaceutically 0372. In certain embodiments, the present invention acceptable Solvate, clathrate, polymorph, or co-crystal relates to the aforementioned pharmaceutical composition, thereof. wherein Said Serotonin reuptake inhibitor is fluoxetine, flu Voxamine, milnacipran, or paroxetine, or a pharmaceutically 0382 Another aspect of the present invention relates to a acceptable Salt, Solvate, clathrate, polymorph, or co-crystal method of treating a patient Suffering from a Sleep abnor of any one of them. mality, comprising the Step of co-administering to a patient in need thereof a therapeutically effective amount of eSZopi 0373) In certain embodiments, the present invention clone, or a pharmaceutically acceptable Salt, Solvate, clath relates to the aforementioned pharmaceutical composition, rate, polymorph, or co-crystal thereof; a therapeutically wherein Said Serotonin reuptake inhibitor is fluoxetine, par effective amount of a Serotonin reuptake inhibitor; and at oxetine, or a pharmaceutically acceptable Salt, Solvate, clath least one pharmaceutically acceptable carrier. rate, polymorph, or co-crystal of either of them. 0383 Another aspect of the present invention relates to a 0374. In certain embodiments, the present invention method of treating a patient Suffering from a Sleep abnor relates to the aforementioned pharmaceutical composition, mality, comprising the Step of co-administering to a patient wherein Said Serotonin reuptake inhibitor is fluoxetine, or a in need thereof a therapeutically effective amount of eSZopi pharmaceutically acceptable Salt, Solvate, clathrate, poly clone, or a pharmaceutically acceptable Salt, Solvate, clath morph, or co-crystal thereof. rate, polymorph, or co-crystal thereof; a therapeutically 0375. In certain embodiments, the present invention effective amount of a Serotonin reuptake inhibitor, wherein relates to the aforementioned pharmaceutical composition, Said Serotonin reuptake inibitor is citalopram, dulloxetine, wherein Said fluoxetine is fluoxetine hydrochloride, or a escitalopram, fluoxetine, fluvoxamine, milnacipran, paroX pharmaceutically acceptable Solvate, clathrate, polymorph, etine, Sertraline, clominpramine, femoxetine, indapline, ala or co-crystal thereof. prolclate, cericlamine, or ifoxetine, or a pharmaceutically acceptable Salt, Solvate, clathrate, polymorph, or co-crystal 0376 Another aspect of the present invention relates to a of any one of them; and at least one pharmaceutically method of treating a patient Suffering from a Sleep abnor acceptable carrier. mality, comprising the Step of co-administering to a patient in need thereof a therapeutically effective amount of eSZopi 0384. In certain embodiments, the present invention clone, or a pharmaceutically acceptable Salt, Solvate, clath relates to the aforementioned method, wherein Said Seroto rate, polymorph, or co-crystal thereof, and a therapeutically nin reuptake inhibitor is fluoxetine, fluvoxamine, milnacip effective amount of a Serotonin reuptake inhibitor. ran, or paroxetine, or a pharmaceutically acceptable Salt, Solvate, clathrate, polymorph, or co-crystal of any one of 0377 Another aspect of the present invention relates to a them. method of treating a patient Suffering from a Sleep abnor mality, comprising the Step of co-administering to a patient 0385) In certain embodiments, the present invention in need thereof a therapeutically effective amount of eSZopi relates to the aforementioned method, wherein Said Seroto clone, or a pharmaceutically acceptable Salt, Solvate, clath nin reuptake inhibitor is fluoxetine, paroxetine, or a phar rate, polymorph, or co-crystal thereof, and a therapeutically maceutically acceptable Salt, Solvate, clathrate, polymorph, effective amount of a Serotonin reuptake inhibitor, wherein or co-crystal of either of them. Said Serotonin reuptake inibitor is citalopram, dulloxetine, 0386. In certain embodiments, the present invention escitalopram, fluoxetine, fluvoxamine, milnacipran, paroX relates to the aforementioned method, wherein Said Seroto etine, Sertraline, clominpramine, femoxetine, indapline, ala nin reuptake inhibitor is fluoxetine, or a pharmaceutically prolclate, cericlamine, or ifoxetine, or a pharmaceutically acceptable Salt, Solvate, clathrate, polymorph, or co-crystal acceptable Salt, Solvate, clathrate, polymorph, or co-crystal thereof. of any one of them. 0387. In certain embodiments, the present invention 0378. In certain embodiments, the present invention relates to the aforementioned method, wherein Said fluox relates to the aforementioned method, wherein Said Seroto etine is fluoxetine hydrochloride, or a pharmaceutically nin reuptake inhibitor is fluoxetine, fluvoxamine, milnacip acceptable Solvate, clathrate, polymorph, or co-crystal ran, or paroxetine, or a pharmaceutically acceptable Salt, thereof. Solvate, clathrate, polymorph, or co-crystal of any one of them. 0388. In certain embodiments, the present invention relates to the aforementioned method, wherein Said Sleep 0379. In certain embodiments, the present invention abnormality is difficulty falling asleep, difficulty staying relates to the aforementioned method, wherein Said Seroto asleep, or waking up too early. US 2005/0176680 A1 Aug. 11, 2005 45

0389 Another aspect of the present invention relates to a acceptable Salt, Solvate, clathrate, polymorph, or co-crystal method of treating a patient Suffering from insomnia, com of any one of them; and at least one pharmaceutically prising the Step of co-administering to a patient in need acceptable carrier. thereof a therapeutically effective amount of eSZopiclone, or a pharmaceutically acceptable Salt, Solvate, clathrate, poly 0397. In certain embodiments, the present invention relates to the aforementioned method, wherein Said Seroto morph, or co-crystal thereof, and a therapeutically effective nin reuptake inhibitor is fluoxetine, fluvoxamine, milnacip amount of a Serotonin reuptake inhibitor. ran, or paroxetine, or a pharmaceutically acceptable Salt, 0390 Another aspect of the present invention relates to a Solvate, clathrate, polymorph, or co-crystal of any one of method of treating a patient Suffering from insomnia, com them. prising the Step of co-administering to a patient in need 0398. In certain embodiments, the present invention thereof a therapeutically effective amount of eSZopiclone, or relates to the aforementioned method, wherein Said Seroto a pharmaceutically acceptable Salt, Solvate, clathrate, poly nin reuptake inhibitor is fluoxetine, paroxetine, or a phar morph, or co-crystal thereof, and a therapeutically effective maceutically acceptable Salt, Solvate, clathrate, polymorph, amount of a Serotonin reuptake inhibitor, wherein Said Serotonin reuptake inibitor is citalopram, dulloxetine, escit or co-crystal of either of them. allopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, 0399. In certain embodiments, the present invention Sertraline, clominpramine, femoxetine, indapline, alapro relates to the aforementioned method, wherein Said Seroto lclate, cericlamine, or ifoxetine, or a pharmaceutically nin reuptake inhibitor is fluoxetine, or a pharmaceutically acceptable Salt, Solvate, clathrate, polymorph, or co-crystal acceptable Salt, Solvate, clathrate, polymorph, or co-crystal of any one of them. thereof. 0391) In certain embodiments, the present invention 0400. In certain embodiments, the present invention relates to the aforementioned method, wherein Said Seroto relates to the aforementioned method, wherein Said fluox nin reuptake inhibitor is fluoxetine, fluvoxamine, milnacip etine is fluoxetine hydrochloride, or a pharmaceutically ran, or paroxetine, or a pharmaceutically acceptable Salt, acceptable Solvate, clathrate, polymorph, or co-crystal Solvate, clathrate, polymorph, or co-crystal of any one of thereof. them. 04.01. In certain embodiments, the present invention 0392. In certain embodiments, the present invention relates to the aforementioned method, wherein Said insom relates to the aforementioned method, wherein Said Seroto nia is transient insomnia. nin reuptake inhibitor is fluoxetine, paroxetine, or a phar 0402. In certain embodiments, the present invention maceutically acceptable Salt, Solvate, clathrate, polymorph, relates to the aforementioned method, wherein Said insom or co-crystal of either of them. nia is short-term insomnia. 0393. In certain embodiments, the present invention 0403. In certain embodiments, the present invention relates to the aforementioned method, wherein Said Seroto relates to the aforementioned method, wherein Said insom nin reuptake inhibitor is fluoxetine, or a pharmaceutically nia is chronic insomnia. acceptable Salt, Solvate, clathrate, polymorph, or co-crystal thereof. 0404 Another aspect of the present invention relates to a method of treating a patient Suffering from depression, 0394. In certain embodiments, the present invention comprising the Step of co-administering to a patient in need relates to the aforementioned method, wherein Said fluox thereof a therapeutically effective amount of eSZopiclone, or etine is fluoxetine hydrochloride, or a pharmaceutically a pharmaceutically acceptable Salt, Solvate, clathrate, poly acceptable Solvate, clathrate, polymorph, or co-crystal morph, or co-crystal thereof, and a therapeutically effective thereof. amount of a Serotonin reuptake inhibitor. 0395. Another aspect of the present invention relates to a 04.05) Another aspect of the present invention relates to a method of treating a patient Suffering from insomnia, com method of treating a patient Suffering from depression, prising the Step of co-administering to a patient in need comprising the Step of co-administering to a patient in need thereof a therapeutically effective amount of eSZopiclone, or thereof a therapeutically effective amount of eSZopiclone, or a pharmaceutically acceptable Salt, Solvate, clathrate, poly a pharmaceutically acceptable Salt, Solvate, clathrate, poly morph, or co-crystal thereof; a therapeutically effective morph, or co-crystal thereof, and a therapeutically effective amount of a Serotonin reuptake inhibitor, and at least one amount of a Serotonin reuptake inhibitor, wherein Said pharmaceutically acceptable carrier. Serotonin reuptake inibitor is citalopram, dulloxetine, escit allopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, 0396 Another aspect of the present invention relates to a Sertraline, clominpramine, femoxetine, indapline, alapro method of treating a patient Suffering from insomnia, com lclate, cericlamine, or ifoxetine, or a pharmaceutically prising the Step of co-administering to a patient in need acceptable Salt, Solvate, clathrate, polymorph, or co-crystal thereof a therapeutically effective amount of eSZopiclone, or a pharmaceutically acceptable Salt, Solvate, clathrate, poly of any one of them. morph, or co-crystal thereof; a therapeutically effective 0406. In certain embodiments, the present invention amount of a Serotonin reuptake inhibitor, wherein Said relates to the aforementioned method, wherein Said Seroto Serotonin reuptake inibitor is citalopram, dulloxetine, escit nin reuptake inhibitor is fluoxetine, fluvoxamine, milnacip allopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, ran, or paroxetine, or a pharmaceutically acceptable Salt, Sertraline, clominpramine, femoxetine, indapline, alapro Solvate, clathrate, polymorph, or co-crystal of any one of lclate, cericlamine, or ifoxetine, or a pharmaceutically them. US 2005/0176680 A1 Aug. 11, 2005 46

0407. In certain embodiments, the present invention 0417. Another aspect of the present invention relates to a relates to the aforementioned method, wherein Said Seroto pharmaceutical composition comprising eSZopiclone, or a nin reuptake inhibitor is fluoxetine, paroxetine, or a phar pharmaceutically acceptable Salt, Solvate, clathrate, poly maceutically acceptable Salt, Solvate, clathrate, polymorph, morph, or co-crystal thereof, and a norepinephrine reuptake or co-crystal of either of them. inhibitor. 0408. In certain embodiments, the present invention 0418. Another aspect of the present invention relates to a relates to the aforementioned method, wherein Said Seroto pharmaceutical composition comprising eSZopiclone, or a nin reuptake inhibitor is fluoxetine, or a pharmaceutically pharmaceutically acceptable Salt, Solvate, clathrate, poly acceptable Salt, Solvate, clathrate, polymorph, or co-crystal morph, or co-crystal thereof, and a norepinephrine reuptake thereof. inhibitor, wherein Said norepinephrine reuptake inhibitor is 04.09. In certain embodiments, the present invention desipramine, maprotiline, lofepramine, reboxetine, Oxapro relates to the aforementioned method, wherein Said fluox tiline, feZolamine, tomoxetine, or (S,S)-hydroxybupropion, etine is fluoxetine hydrochloride, or a pharmaceutically or a pharmaceutically acceptable Salt, Solvate, clathrate, acceptable Solvate, clathrate, polymorph, or co-crystal polymorph, or co-crystal of any one of them. thereof. 0419. In certain embodiments, the present invention 0410 Another aspect of the present invention relates to a relates to the aforementioned pharmaceutical composition, method of treating a patient Suffering from depression, wherein Said norepinephrine reuptake inhibitor is comprising the Step of co-administering to a patient in need desipramine, reboxetine, Oxaprotiline, or (S,S)-hydroxybu thereof a therapeutically effective amount of eSZopiclone, or propion, or a pharmaceutically acceptable Salt, Solvate, a pharmaceutically acceptable Salt, Solvate, clathrate, poly clathrate, polymorph, or co-crystal of any one of them. morph, or co-crystal thereof; a therapeutically effective amount of a Serotonin reuptake inhibitor, and at least one 0420. In certain embodiments, the present invention pharmaceutically acceptable carrier. relates to the aforementioned pharmaceutical composition, 0411) Another aspect of the present invention relates to a wherein said norepinephrine reuptake inhibitor is (S,S)- method of treating a patient Suffering from depression, hydroxybupropion, or a pharmaceutically acceptable Salt, comprising the Step of co-administering to a patient in need Solvate, clathrate, polymorph, or co-crystal thereof. thereof a therapeutically effective amount of eSZopiclone, or 0421) Another aspect of the present invention relates to a a pharmaceutically acceptable Salt, Solvate, clathrate, poly pharmaceutical composition consisting essentially of morph, or co-crystal thereof; a therapeutically effective eSZopiclone, or a pharmaceutically acceptable Salt, Solvate, amount of a Serotonin reuptake inhibitor, wherein Said clathrate, polymorph, or co-crystal thereof; a norepinephrine Serotonin reuptake inibitor is citalopram, dulloxetine, escit reuptake inhibitor; and at least one pharmaceutically accept allopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, able carrier. Sertraline, clominpramine, femoxetine, indapline, alapro lclate, cericlamine, or ifoxetine, or a pharmaceutically 0422 Another aspect of the present invention relates to a acceptable Salt, Solvate, clathrate, polymorph, or co-crystal pharmaceutical composition consisting essentially of of any one of them; and at least one pharmaceutically eSZopiclone, or a pharmaceutically acceptable Salt, Solvate, acceptable carrier. clathrate, polymorph, or co-crystal thereof; a norepinephrine 0412. In certain embodiments, the present invention reuptake inhibitor, wherein Said norepinephrine reuptake relates to the aforementioned method, wherein Said Seroto inhibitor is desipramine, maprotiline, lofepramine, reboxet nin reuptake inhibitor is fluoxetine, fluvoxamine, milnacip ine, Oxaprotiline, feZolamine, tomoxetine, or (S,S)-hydroxy ran, or paroxetine, or a pharmaceutically acceptable Salt, bupropion, or a pharmaceutically acceptable Salt, Solvate, Solvate, clathrate, polymorph, or co-crystal of any one of clathrate, polymorph, or co-crystal of any one of them; and them. at least one pharmaceutically acceptable carrier. 0413. In certain embodiments, the present invention 0423 In certain embodiments, the present invention relates to the aforementioned method, wherein Said Seroto relates to the aforementioned pharmaceutical composition, nin reuptake inhibitor is fluoxetine, paroxetine, or a phar wherein Said norepinephrine reuptake inhibitor is maceutically acceptable Salt, Solvate, clathrate, polymorph, desipramine, reboxetine, Oxaprotiline, or (S,S)-hydroxybu or co-crystal of either of them. propion, or a pharmaceutically acceptable Salt, Solvate, clathrate, polymorph, or co-crystal of any one of them. 0414. In certain embodiments, the present invention relates to the aforementioned method, wherein Said Seroto 0424. In certain embodiments, the present invention nin reuptake inhibitor is fluoxetine, or a pharmaceutically relates to the aforementioned pharmaceutical composition, acceptable Salt, Solvate, clathrate, polymorph, or co-crystal wherein said norepinephrine reuptake inhibitor is (S,S)- thereof. hydroxybupropion, or a pharmaceutically acceptable Salt, 0415. In certain embodiments, the present invention Solvate, clathrate, polymorph, or co-crystal thereof. relates to the aforementioned method, wherein Said fluox 0425. Another aspect of the present invention relates to a etine is fluoxetine hydrochloride, or a pharmaceutically method of treating a patient Suffering from a Sleep abnor acceptable Solvate, clathrate, polymorph, or co-crystal mality, comprising the Step of co-administering to a patient thereof. in need thereof a therapeutically effective amount of eSZopi 0416) In certain embodiments, the present invention clone, or a pharmaceutically acceptable Salt, Solvate, clath relates to the aforementioned method, wherein Said depres rate, polymorph, or co-crystal thereof, and a therapeutically Sion is a major depressive disorder. effective amount of norepinephrine reuptake inhibitor. US 2005/0176680 A1 Aug. 11, 2005 47

0426. Another aspect of the present invention relates to a prising the Step of co-administering to a patient in need method of treating a patient Suffering from a Sleep abnor thereof a therapeutically effective amount of eSZopiclone, or mality, comprising the Step of co-administering to a patient a pharmaceutically acceptable Salt, Solvate, clathrate, poly in need thereof a therapeutically effective amount of eSZopi morph, or co-crystal thereof, and a therapeutically effective clone, or a pharmaceutically acceptable Salt, Solvate, clath amount of norepinephrine reuptake inhibitor. rate, polymorph, or co-crystal thereof, and a therapeutically effective amount of norepinephrine reuptake inhibitor, 0435 Another aspect of the present invention relates to a wherein Said norepinephrine reuptake inhibitor is method of treating a patient Suffering from insomnia, com desipramine, maprotiline, lofepramine, reboxetine, Oxapro prising the Step of co-administering to a patient in need tiline, feZolamine, tomoxetine, or (S,S)-hydroxybupropion, thereof a therapeutically effective amount of eSZopiclone, or or a pharmaceutically acceptable Salt, Solvate, clathrate, a pharmaceutically acceptable Salt, Solvate, clathrate, poly polymorph, or co-crystal of any one of them. morph, or co-crystal thereof, and a therapeutically effective amount of norepinephrine reuptake inhibitor, wherein Said 0427. In certain embodiments, the present invention norepinephrine reuptake inhibitor is desipramine, mapro relates to the aforementioned method, wherein Said norepi tiline, lofepramine, reboxetine, Oxaprotiline, feZolamine, nephrine reuptake inhibitor is desipramine, reboxetine, tomoxetine, or (S,S)-hydroxybupropion, or a pharmaceuti Oxaprotiline, or (S,S)-hydroxybupropion, or a pharmaceuti cally acceptable Salt, Solvate, clathrate, polymorph, or co cally acceptable Salt, Solvate, clathrate, polymorph, or co crystal of any one of them. crystal of any one of them. 0436. In certain embodiments, the present invention 0428. In certain embodiments, the present invention relates to the aforementioned method, wherein Said norepi relates to the aforementioned method, wherein Said norepi nephrine reuptake inhibitor is desipramine, reboxetine, nephrine reuptake inhibitor is (S,S)-hydroxybupropion, or a Oxaprotiline, or (S,S)-hydroxybupropion, or a pharmaceuti pharmaceutically acceptable Salt, Solvate, clathrate, poly cally acceptable Salt, Solvate, clathrate, polymorph, or co morph, or co-crystal thereof crystal of any one of them. 0429. Another aspect of the present invention relates to a method of treating a patient Suffering from a Sleep abnor 0437. In certain embodiments, the present invention mality, comprising the Step of co-administering to a patient relates to the aforementioned method, wherein Said norepi in need thereof a therapeutically effective amount of eSZopi nephrine reuptake inhibitor is (S,S)-hydroxybupropion, or a clone, or a pharmaceutically acceptable Salt, Solvate, clath pharmaceutically acceptable Salt, Solvate, clathrate, poly rate, polymorph, or co-crystal thereof; a therapeutically morph, or co-crystal of any one of them. effective amount of norepinephrine reuptake inhibitor; and 0438 Another aspect of the present invention relates to a at least one pharmaceutically acceptable carrier. method of treating a patient Suffering from insomnia, com 0430. Another aspect of the present invention relates to a prising the Step of co-administering to a patient in need method of treating a patient Suffering from a Sleep abnor thereof a therapeutically effective amount of eSZopiclone, or mality, comprising the Step of co-administering to a patient a pharmaceutically acceptable Salt, Solvate, clathrate, poly in need thereof a therapeutically effective amount of eSZopi morph, or co-crystal thereof; a therapeutically effective clone, or a pharmaceutically acceptable Salt, Solvate, clath amount of norepinephrine reuptake inhibitor; and at least rate, polymorph, or co-crystal thereof; a therapeutically one pharmaceutically acceptable carrier. effective amount of norepinephrine reuptake inhibitor, 0439 Another aspect of the present invention relates to a wherein Said norepinephrine reuptake inhibitor is method of treating a patient Suffering from insomnia, com desipramine, maprotiline, lofepramine, reboxetine, Oxapro prising the Step of co-administering to a patient in need tiline, feZolamine, tomoxetine, or (S,S)-hydroxybupropion, thereof a therapeutically effective amount of eSZopiclone, or or a pharmaceutically acceptable Salt, Solvate, clathrate, a pharmaceutically acceptable Salt, Solvate, clathrate, poly polymorph, or co-crystal of any one of them; and at least one morph, or co-crystal thereof; a therapeutically effective pharmaceutically acceptable carrier. amount of norepinephrine reuptake inhibitor, wherein Said 0431. In certain embodiments, the present invention norepinephrine reuptake inhibitor is desipramine, mapro relates to the aforementioned method, wherein Said norepi tiline, lofepramine, reboxetine, Oxaprotiline, feZolamine, nephrine reuptake inhibitor is desipramine, reboxetine, tomoxetine, or (S,S)-hydroxybupropion, or a pharmaceuti Oxaprotiline, or (S,S)-hydroxybupropion, or a pharmaceuti cally acceptable Salt, Solvate, clathrate, polymorph, or co cally acceptable Salt, Solvate, clathrate, polymorph, or co crystal of any one of them; and at least one pharmaceutically crystal of any one of them. acceptable carrier. 0432. In certain embodiments, the present invention 0440. In certain embodiments, the present invention relates to the aforementioned method, wherein Said norepi relates to the aforementioned method, wherein Said norepi nephrine reuptake inhibitor is (S,S)-hydroxybupropion, or a nephrine reuptake inhibitor is desipramine, reboxetine, pharmaceutically acceptable Salt, Solvate, clathrate, poly Oxaprotiline, or (S,S)-hydroxybupropion, or a pharmaceuti morph, or co-crystal thereof. cally acceptable Salt, Solvate, clathrate, polymorph, or co 0433. In certain embodiments, the present invention crystal of any one of them. relates to the aforementioned method, wherein Said Sleep 0441. In certain embodiments, the present invention abnormality is difficulty falling asleep, difficulty staying relates to the aforementioned method, wherein Said norepi asleep, or waking up too early. nephrine reuptake inhibitor is (S,S)-hydroxybupropion, or a 0434. Another aspect of the present invention relates to a pharmaceutically acceptable Salt, Solvate, clathrate, poly method of treating a patient Suffering from insomnia, com morph, or co-crystal of any one of them. US 2005/0176680 A1 Aug. 11, 2005 48

0442. In certain embodiments, the present invention 0451. In certain embodiments, the present invention relates to the aforementioned method, wherein Said insom relates to the aforementioned method, wherein Said norepi nia is transient insomnia. nephrine reuptake inhibitor is desipramine, reboxetine, Oxaprotiline, or (S,S)-hydroxybupropion, or a pharmaceuti 0443) In certain embodiments, the present invention cally acceptable Salt, Solvate, clathrate, polymorph, or co relates to the aforementioned method, wherein Said insom nia is short-term insomnia. crystal of any one of them. 0452. In certain embodiments, the present invention 0444. In certain embodiments, the present invention relates to the aforementioned method, wherein Said norepi relates to the aforementioned method, wherein Said insom nephrine reuptake inhibitor is (S,S)-hydroxybupropion, or a nia is chronic insomnia. pharmaceutically acceptable Salt, Solvate, clathrate, poly 0445 Another aspect of the present invention relates to a morph, or co-crystal of any one of them. method of treating a patient Suffering from depression, comprising the Step of co-administering to a patient in need 0453. In certain embodiments, the present invention thereof a therapeutically effective amount of eSZopiclone, or relates to the aforementioned method, wherein Said depres a pharmaceutically acceptable Salt, Solvate, clathrate, poly Sion is a major depressive disorder. morph, or co-crystal thereof, and a therapeutically effective 0454. Another aspect of the present invention relates to a amount of norepinephrine reuptake inhibitor. pharmaceutical composition comprising eSZopiclone, or a 0446. Another aspect of the present invention relates to a pharmaceutically acceptable Salt, Solvate, clathrate, poly method of treating a patient Suffering from depression, morph, or co-crystal thereof, and a dopamine reuptake comprising the Step of co-administering to a patient in need inhibitor. thereof a therapeutically effective amount of eSZopiclone, or 0455 Another aspect of the present invention relates to a a pharmaceutically acceptable Salt, Solvate, clathrate, poly pharmaceutical composition comprising eSZopiclone, or a morph, or co-crystal thereof, and a therapeutically effective pharmaceutically acceptable Salt, Solvate, clathrate, poly amount of norepinephrine reuptake inhibitor, wherein Said morph, or co-crystal thereof, and a dopamine reuptake norepinephrine reuptake inhibitor is desipramine, mapro inhibitor, Said dopamine reuptake inhibitor is amineptine, tiline, lofepramine, reboxetine, Oxaprotiline, feZolamine, bupropion, GBR-12935, venlafaxine, desmethylvenlafax tomoxetine, or (S,S)-hydroxybupropion, or a pharmaceuti ine, or 2,3-propanoyl-3?-(4-tolyl)-tropane, or a pharmaceu cally acceptable Salt, Solvate, clathrate, polymorph, or co tically acceptable Salt, Solvate, clathrate, polymorph, or crystal of any one of them. co-crystal of any one of them. 0447. In certain embodiments, the present invention 0456. In certain embodiments, the present invention relates to the aforementioned method, wherein Said norepi relates to the aforementioned pharmaceutical composition, nephrine reuptake inhibitor is desipramine, reboxetine, wherein Said dopamine reuptake inhibitor is bupropion, or Oxaprotiline, or (S,S)-hydroxybupropion, or a pharmaceuti GBR-12935, or a pharmaceutically acceptable salt, Solvate, cally acceptable Salt, Solvate, clathrate, polymorph, or co clathrate, polymorph, or co-crystal of either of them. crystal of any one of them. 0457. In certain embodiments, the present invention 0448. In certain embodiments, the present invention relates to the aforementioned pharmaceutical composition, relates to the aforementioned method, wherein Said norepi wherein Said dopamine reuptake inhibitor is bupropion, or a nephrine reuptake inhibitor is (S,S)-hydroxybupropion, or a pharmaceutically acceptable Salt, Solvate, clathrate, poly pharmaceutically acceptable Salt, Solvate, clathrate, poly morph, or co-crystal thereof. morph, or co-crystal of any one of them. 0458 In certain embodiments, the present invention 0449 Another aspect of the present invention relates to a relates to the aforementioned pharmaceutical composition, method of treating a patient Suffering from depression, wherein Said dopamine reuptake inhibitor is Venlafaxine, comprising the Step of co-administering to a patient in need deSmethylvenlafaxine, or a pharmaceutically acceptable thereof a therapeutically effective amount of eSZopiclone, or Salt, Solvate, clathrate, polymorph, or co-crystal of either of a pharmaceutically acceptable Salt, Solvate, clathrate, poly them. morph, or co-crystal thereof; a therapeutically effective 0459. In certain embodiments, the present invention amount of norepinephrine reuptake inhibitor; and at least relates to the aforementioned pharmaceutical composition, one pharmaceutically acceptable carrier. wherein Said desmethylvenlafaxine is racemic desmethyl 0450 Another aspect of the present invention relates to a Venlafaxine, (+)-desmethylvenlafaxine, or (-)-desmethyl method of treating a patient Suffering from depression, Venlafaxine, or a pharmaceutically acceptable Salt, Solvate, comprising the Step of co-administering to a patient in need clathrate, polymorph, or co-crystal of any one of them. thereof a therapeutically effective amount of eSZopiclone, or 0460 Another aspect of the present invention relates to a a pharmaceutically acceptable Salt, Solvate, clathrate, poly pharmaceutical composition consisting essentially of morph, or co-crystal thereof; a therapeutically effective eSZopiclone, or a pharmaceutically acceptable Salt, Solvate, amount of norepinephrine reuptake inhibitor, wherein Said norepinephrine reuptake inhibitor is desipramine, mapro clathrate, polymorph, or co-crystal thereof; a dopamine tiline, lofepramine, reboxetine, Oxaprotiline, feZolamine, reuptake inhibitor; and at least one pharmaceutically accept tomoxetine, or (S,S)-hydroxybupropion, or a pharmaceuti able carrier. cally acceptable Salt, Solvate, clathrate, polymorph, or co 0461) Another aspect of the present invention relates to a crystal of any one of them; and at least one pharmaceutically pharmaceutical composition consisting essentially of acceptable carrier. eSZopiclone, or a pharmaceutically acceptable Salt, Solvate, US 2005/0176680 A1 Aug. 11, 2005 49 clathrate, polymorph, or co-crystal thereof; a dopamine ine reuptake inhibitor is Venlafaxine, desmethylvenlafaxine, reuptake inhibitor, Said dopamine reuptake inhibitor is or a pharmaceutically acceptable Salt, Solvate, clathrate, amineptine, bupropion, GBR-12935, Venlafaxine, desmeth polymorph, or co-crystal of either of them. ylvenlafaxine, or 2(3-propanoyl-3?-(4-tolyl)-tropane, or a 0471. In certain embodiments, the present invention pharmaceutically acceptable Salt, Solvate, clathrate, poly relates to the aforementioned method, wherein Said desm morph, or co-crystal of any one of them; and at least one ethylvenlafaxine is racemic desmethylvenlafaxine, (+)-des pharmaceutically acceptable carrier. methylvenlafaxine, or (-)-desmethylvenlafaxine, or a phar 0462. In certain embodiments, the present invention maceutically acceptable Salt, Solvate, clathrate, polymorph, relates to the aforementioned pharmaceutical composition, or co-crystal of any one of them. wherein Said dopamine reuptake inhibitor is bupropion, or 0472. Another aspect of the present invention relates to a GBR-12935, or a pharmaceutically acceptable salt, Solvate, method of treating a patient Suffering from a Sleep abnor clathrate, polymorph, or co-crystal of either of them. mality, comprising the Step of co-administering to a patient 0463. In certain embodiments, the present invention in need thereof a therapeutically effective amount of eSZopi relates to the aforementioned pharmaceutical composition, clone, or a pharmaceutically acceptable Salt, Solvate, clath wherein Said dopamine reuptake inhibitor is bupropion, or a rate, polymorph, or co-crystal thereof, a therapeutically pharmaceutically acceptable Salt, Solvate, clathrate, poly effective amount of a dopamine reuptake inhibitor; and at morph, or co-crystal thereof. least one pharmaceutically acceptable carrier. 0464) In certain embodiments, the present invention 0473 Another aspect of the present invention relates to a relates to the aforementioned pharmaceutical composition, method of treating a patient Suffering from a Sleep abnor wherein Said dopamine reuptake inhibitor is Venlafaxine, mality, comprising the Step of co-administering to a patient deSmethylvenlafaxine, or a pharmaceutically acceptable in need thereof a therapeutically effective amount of eSZopi Salt, Solvate, clathrate, polymorph, or co-crystal of either of clone, or a pharmaceutically acceptable Salt, Solvate, clath them. rate, polymorph, or co-crystal thereof; a therapeutically effective amount of a dopamine reuptake inhibitor, wherein 0465. In certain embodiments, the present invention Said dopamine reuptake inhibitor is amineptine, bupropion, relates to the aforementioned pharmaceutical composition, GBR-12935, venlafaxine, desmethylvenlafaxine, or 23-pro wherein Said desmethylvenlafaxine is racemic desmethyl panoyl-3?-(4-tolyl)-tropane, or a pharmaceutically accept venlafaxine, (+)-desmethylvenlafaxine, or (-)-desmethyl able Salt, Solvate, clathrate, polymorph, or co-crystal of any Venlafaxine, or a pharmaceutically acceptable Salt, Solvate, one of them; and at least one pharmaceutically acceptable clathrate, polymorph, or co-crystal of any one of them. carrier. 0466 Another aspect of the present invention relates to a method of treating a patient Suffering from a Sleep abnor 0474. In certain embodiments, the present invention mality, comprising the Step of co-administering to a patient relates to the aforementioned method, wherein Said dopam in need thereof a therapeutically effective amount of eSZopi ine reuptake inhibitor is bupropion, or GBR-12935, or a clone, or a pharmaceutically acceptable Salt, Solvate, clath pharmaceutically acceptable Salt, Solvate, clathrate, poly rate, polymorph, or co-crystal thereof, and a therapeutically morph, or co-crystal of either of them. effective amount of a dopamine reuptake inhibitor. 0475. In certain embodiments, the present invention 0467 Another aspect of the present invention relates to a relates to the aforementioned method, wherein Said dopam method of treating a patient Suffering from a Sleep abnor ine reuptake inhibitor is bupropion, or a pharmaceutically mality, comprising the Step of co-administering to a patient acceptable Salt, Solvate, clathrate, polymorph, or co-crystal in need thereof a therapeutically effective amount of eSZopi thereof. clone, or a pharmaceutically acceptable Salt, Solvate, clath 0476. In certain embodiments, the present invention rate, polymorph, or co-crystal thereof, and a therapeutically relates to the aforementioned method, wherein Said dopam effective amount of a dopamine reuptake inhibitor, wherein ine reuptake inhibitor is Venlafaxine, desmethylvenlafaxine, Said dopamine reuptake inhibitor is amineptine, bupropion, or a pharmaceutically acceptable Salt, Solvate, clathrate, GBR-12935, venlafaxine, desmethylvenlafaxine, or 23-pro polymorph, or co-crystal of either of them. panoyl-3?-(4-tolyl)-tropane, or a pharmaceutically accept 0477. In certain embodiments, the present invention able Salt, Solvate, clathrate, polymorph, or co-crystal of any relates to the aforementioned method, wherein Said desm one of them. ethylvenlafaxine is racemic desmethylvenlafaxine, (+)-des 0468. In certain embodiments, the present invention methylvenlafaxine, or (-)-desmethylvenlafaxine, or a phar relates to the aforementioned method, wherein Said dopam maceutically acceptable Salt, Solvate, clathrate, polymorph, ine reuptake inhibitor is bupropion, or GBR-12935, or a or co-crystal of any one of them. pharmaceutically acceptable Salt, Solvate, clathrate, poly morph, or co-crystal of either of them. 0478. In certain embodiments, the present invention relates to the aforementioned method, wherein Said Sleep 0469. In certain embodiments, the present invention abnormality is difficulty falling asleep, difficulty staying relates to the aforementioned method, wherein Said dopam asleep, or waking up too early. ine reuptake inhibitor is bupropion, or a pharmaceutically 0479. Another aspect of the present invention relates to a acceptable Salt, Solvate, clathrate, polymorph, or co-crystal method of treating a patient Suffering from insomnia, com thereof. prising the Step of co-administering to a patient in need 0470. In certain embodiments, the present invention thereof a therapeutically effective amount of eSZopiclone, or relates to the aforementioned method, wherein Said dopam a pharmaceutically acceptable Salt, Solvate, clathrate, poly US 2005/0176680 A1 Aug. 11, 2005 50 morph, or co-crystal thereof, and a therapeutically effective pharmaceutically acceptable Salt, Solvate, clathrate, poly amount of a dopamine reuptake inhibitor. morph, or co-crystal of either of them. 0480. Another aspect of the present invention relates to a 0488. In certain embodiments, the present invention method of treating a patient Suffering from insomnia, com relates to the aforementioned method, wherein Said dopam prising the Step of co-administering to a patient in need ine reuptake inhibitor is bupropion, or a pharmaceutically thereof a therapeutically effective amount of eSZopiclone, or acceptable Salt, Solvate, clathrate, polymorph, or co-crystal a pharmaceutically acceptable Salt, Solvate, clathrate, poly thereof. morph, or co-crystal thereof, and a therapeutically effective 0489. In certain embodiments, the present invention amount of a dopamine reuptake inhibitor, wherein Said relates to the aforementioned method, wherein Said dopam dopamine reuptake inhibitor is amineptine, bupropion, ine reuptake inhibitor is Venlafaxine, desmethylvenlafaxine, GBR-12935, venlafaxine, desmethylvenlafaxine, or 23-pro or a pharmaceutically acceptable Salt, Solvate, clathrate, panoyl-3?-(4-tolyl)-tropane, or a pharmaceutically accept polymorph, or co-crystal of either of them. able Salt, Solvate, clathrate, polymorph, or co-crystal of any one of them. 0490. In certain embodiments, the present invention relates to the aforementioned method, wherein Said desm 0481. In certain embodiments, the present invention ethylvenlafaxine is racemic desmethylvenlafaxine, (+)-des relates to the aforementioned method, wherein Said dopam methylvenlafaxine, or (-)-desmethylvenlafaxine, or a phar ine reuptake inhibitor is bupropion, or GBR-12935, or a maceutically acceptable Salt, Solvate, clathrate, polymorph, pharmaceutically acceptable Salt, Solvate, clathrate, poly or co-crystal of any one of them. morph, or co-crystal of either of them. 0491 In certain embodiments, the present invention 0482 In certain embodiments, the present invention relates to the aforementioned method, wherein Said insom relates to the aforementioned method, wherein Said dopam nia is transient insomnia. ine reuptake inhibitor is bupropion, or a pharmaceutically 0492. In certain embodiments, the present invention acceptable Salt, Solvate, clathrate, polymorph, or co-crystal relates to the aforementioned method, wherein Said insom thereof. nia is short-term insomnia. 0483. In certain embodiments, the present invention 0493. In certain embodiments, the present invention relates to the aforementioned method, wherein Said dopam relates to the aforementioned method, wherein Said insom ine reuptake inhibitor is Venlafaxine, desmethylvenlafaxine, nia is chronic insomnia. or a pharmaceutically acceptable Salt, Solvate, clathrate, polymorph, or co-crystal of either of them. 0494. Another aspect of the present invention relates to a method of treating a patient Suffering from depression, 0484. In certain embodiments, the present invention comprising the Step of co-administering to a patient in need relates to the aforementioned method, wherein Said desm thereof a therapeutically effective amount of eSZopiclone, or ethylvenlafaxine is racemic desmethylvenlafaxine, (+)-des a pharmaceutically acceptable Salt, Solvate, clathrate, poly methylvenlafaxine, or (-)-desmethylvenlafaxine, or a phar morph, or co-crystal thereof, and a therapeutically effective maceutically acceptable Salt, Solvate, clathrate, polymorph, amount of a dopamine reuptake inhibitor. or co-crystal of any one of them. 0495. Another aspect of the present invention relates to a 0485 Another aspect of the present invention relates to a method of treating a patient Suffering from depression, method of treating a patient Suffering from insomnia, com comprising the Step of co-administering to a patient in need prising the Step of co-administering to a patient in need thereof a therapeutically effective amount of eSZopiclone, or thereof a therapeutically effective amount of eSZopiclone, or a pharmaceutically acceptable Salt, Solvate, clathrate, poly a pharmaceutically acceptable Salt, Solvate, clathrate, poly morph, or co-crystal thereof, and a therapeutically effective morph, or co-crystal thereof; a therapeutically effective amount of a dopamine reuptake inhibitor, wherein Said amount of a dopamine reuptake inhibitor; and at least one dopamine reuptake inhibitor is amineptine, bupropion, pharmaceutically acceptable carrier. GBR-12935, venlafaxine, desmethylvenlafaxine, or 23-pro panoyl-3?-(4-tolyl)-tropane, or a pharmaceutically accept 0486. Another aspect of the present invention relates to a able Salt, Solvate, clathrate, polymorph, or co-crystal of any method of treating a patient Suffering from insomnia, com one of them. prising the Step of co-administering to a patient in need thereof a therapeutically effective amount of eSZopiclone, or 0496. In certain embodiments, the present invention a pharmaceutically acceptable Salt, Solvate, clathrate, poly relates to the aforementioned method, wherein Said dopam morph, or co-crystal thereof; a therapeutically effective ine reuptake inhibitor is bupropion, or GBR-12935, or a amount of a dopamine reuptake inhibitor, wherein Said pharmaceutically acceptable Salt, Solvate, clathrate, poly dopamine reuptake inhibitor is amineptine, bupropion, morph, or co-crystal of either of them. GBR-12935, venlafaxine, desmethylvenlafaxine, or 23-pro 0497. In certain embodiments, the present invention panoyl-3?-(4-tolyl)-tropane, or a pharmaceutically accept relates to the aforementioned method, wherein Said dopam able Salt, Solvate, clathrate, polymorph, or co-crystal of any ine reuptake inhibitor is bupropion, or a pharmaceutically one of them; and at least one pharmaceutically acceptable acceptable Salt, Solvate, clathrate, polymorph, or co-crystal carrier. thereof. 0487. In certain embodiments, the present invention 0498. In certain embodiments, the present invention relates to the aforementioned method, wherein Said dopam relates to the aforementioned method, wherein Said dopam ine reuptake inhibitor is bupropion, or GBR-12935, or a ine reuptake inhibitor is Venlafaxine, desmethylvenlafaxine, US 2005/0176680 A1 Aug. 11, 2005 or a pharmaceutically acceptable Salt, Solvate, clathrate, 0509. In certain embodiments, the present invention polymorph, or co-crystal of either of them. relates to the aforementioned pharmaceutical composition, 0499. In certain embodiments, the present invention wherein the 5-HTA modulator is a 5-HTA inverse agonist. relates to the aforementioned method, wherein Said desm 0510) Another aspect of the present invention relates to a ethylvenlafaxine is racemic desmethylvenlafaxine, (+)-des pharmaceutical composition comprising eSZopiclone, or a methylvenlafaxine, or (-)-desmethylvenlafaxine, or a phar pharmaceutically acceptable Salt, Solvate, clathrate, poly maceutically acceptable Salt, Solvate, clathrate, polymorph, morph, or co-crystal thereof, and a 5-HT2A modulator, or co-crystal of any one of them. wherein said 5 HTA modulator is MDL 100907, SR 0500 Another aspect of the present invention relates to a 46349B, YM 992, fananserin, oxazolidine compounds A, method of treating a patient Suffering from depression, phenylindole compounds A, piperidinyl compounds B, comprising the Step of co-administering to a patient in need Spiroazacyclic compounds C, or azacyclic compounds D, or thereof a therapeutically effective amount of eSZopiclone, or a pharmaceutically acceptable Salt, Solvate, clathrate, poly a pharmaceutically acceptable Salt, Solvate, clathrate, poly morph, or co-crystal of any one of them. morph, or co-crystal thereof; a therapeutically effective 0511. In certain embodiments, the present invention amount of a dopamine reuptake inhibitor; and at least one relates to the aforementioned pharmaceutical composition, pharmaceutically acceptable carrier. wherein said 5-HT modulator is MDL 100907, SR 0501) Another aspect of the present invention relates to a 46349B, YM 992, fananserin, oxazolidine compounds A, or method of treating a patient Suffering from depression, phenylindole compounds A, or a pharmaceutically accept comprising the Step of co-administering to a patient in need able Salt, Solvate, clathrate, polymorph, or co crystal of any thereof a therapeutically effective amount of eSZopiclone, or one of them. a pharmaceutically acceptable Salt, Solvate, clathrate, poly 0512. In certain embodiments, the present invention morph, or co-crystal thereof; a therapeutically effective relates to the aforementioned pharmaceutical composition, amount of a dopamine reuptake inhibitor, wherein Said dopamine reuptake inhibitor is amineptine, bupropion, wherein said 5-HT modulator is MDL 100907, SR GBR-12935, venlafaxine, desmethylvenlafaxine, or 23-pro 46349B, YM 992, or fananserin, or a pharmaceutically panoyl-3?-(4-tolyl)-tropane, or a pharmaceutically accept acceptable Salt, Solvate, clathrate, polymorph, or co-crystal able Salt, Solvate, clathrate, polymorph, or co-crystal of any of any one of them. one of them, and at least one pharmaceutically acceptable 0513. In certain embodiments, the present invention carrier. relates to the aforementioned pharmaceutical composition, 0502. In certain embodiments, the present invention wherein Said 5-HTA modulator, wherein Said 5-HT2A relates to the aforementioned method, wherein Said dopam modulator is piperidinyl compounds B, Spiroazacyclic com ine reuptake inhibitor is bupropion, or GBR-12935, or a pounds C, or azacyclic compounds D, or a pharmaceutically pharmaceutically acceptable Salt, Solvate, clathrate, poly acceptable Salt, Solvate, clathrate, polymorph, or co-crystal morph, or co-crystal of either of them. of any one of them. 0503. In certain embodiments, the present invention 0514) Another aspect of the present invention relates to a relates to the aforementioned method, wherein Said dopam pharmaceutical composition consisting essentially of ine reuptake inhibitor is bupropion, or a pharmaceutically eSZopiclone, or a pharmaceutically acceptable Salt, Solvate, acceptable Salt, Solvate, clathrate, polymorph, or co-crystal clathrate, polymorph, or co-crystal thereof; a 5-HTA modu thereof. lator; and at least one pharmaceutically acceptable carrier. 0504. In certain embodiments, the present invention 0515. In certain embodiments, the present invention relates to the aforementioned method, wherein Said dopam relates to the aforementioned pharmaceutical composition, ine reuptake inhibitor is Venlafaxine, desmethylvenlafaxine, wherein the 5-HT modulator is a 5-HT, antagonist. or a pharmaceutically acceptable Salt, Solvate, clathrate, 0516. In certain embodiments, the present invention polymorph, or co-crystal of either of them. relates to the aforementioned pharmaceutical composition, 0505. In certain embodiments, the present invention wherein the 5-HTA modulator is a 5-HTA inverse agonist. relates to the aforementioned method, wherein Said desm ethylvenlafaxine is racemic desmethylvenlafaxine, (+)-des 0517. Another aspect of the present invention relates to a methylvenlafaxine, or (-)-desmethylvenlafaxine, or a phar pharmaceutical composition consisting essentially of maceutically acceptable Salt, Solvate, clathrate, polymorph, eSZopiclone, or a pharmaceutically acceptable Salt, Solvate, or co-crystal of any one of them. clathrate, polymorph, or co-crystal thereof; a 5-HTA modu lator, wherein said 5 HTA modulator is MDL 100907, SR 0506. In certain embodiments, the present invention 46349B, YM 992, fananserin, oxazolidine compounds A, relates to the aforementioned method, wherein Said depres phenylindole compounds A, piperidinyl compounds B, Sion is a major depressive disorder. Spiroazacyclic compounds C, or azacyclic compounds D, or 0507 Another aspect of the present invention relates to a a pharmaceutically acceptable Salt, Solvate, clathrate, poly pharmaceutical composition comprising eSZopiclone, or a morph, or co-crystal of any one of them; and at least one pharmaceutically acceptable Salt, Solvate, clathrate, poly pharmaceutically acceptable carrier. morph, or co-crystal thereof, and a 5-HTA modulator. 0518. In certain embodiments, the present invention 0508. In certain embodiments, the present invention relates to the aforementioned pharmaceutical composition, relates to the aforementioned pharmaceutical composition, wherein said 5-HT modulator is MDL 100907, SR wherein the 5-HTA modulator is a 5-HT2A antagonist. 46349B, YM 992, fananserin, oxazolidine compounds A, or US 2005/0176680 A1 Aug. 11, 2005 52 phenylindole compounds A, or a pharmaceutically accept 0528. Another aspect of the present invention relates to a able Salt, Solvate, clathrate, polymorph, or co-crystal of any method of treating a patient Suffering from a Sleep abnor one of them. mality, comprising the Step of co-administering to a patient in need thereof a therapeutically effective amount of eSZopi 0519 In certain embodiments, the present invention clone, or a pharmaceutically acceptable Salt, Solvate, clath relates to the aforementioned pharmaceutical composition, rate, polymorph, or co-crystal thereof; a therapeutically wherein said 5-HT, modulator is MDL 100907, SR effective amount of a 5-HT, modulator, and at least one 46349B, YM 992, or fananserin, or a pharmaceutically pharmaceutically acceptable carrier. acceptable Salt, Solvate, clathrate, polymorph, or co-crystal of any one of them. 0529. In certain embodiments, the present invention 0520. In certain embodiments, the present invention relates to the aforementioned method, wherein the 5-HT2A relates to the aforementioned pharmaceutical composition, modulator is a 5-HT, antagonist. wherein Said 5-HTA modulator, wherein Said 5 HTA modu 0530 In certain embodiments, the present invention lator is piperidinyl compounds B, Spiroazacyclic compounds relates to the aforementioned method, wherein the 5-HT C, or azacyclic compounds D, or a pharmaceutically accept modulator is a 5-HT2A inverse agonist. able Salt, Solvate, clathrate, polymorph, or co-crystal of any 0531. Another aspect of the present invention relates to a one of them. method of treating a patient Suffering from a Sleep abnor 0521. Another aspect of the present invention relates to a mality, comprising the Step of co-administering to a patient method of treating a patient Suffering from a Sleep abnor in need thereof a therapeutically effective amount of eSZopi mality, comprising the Step of co-administering to a patient clone, or a pharmaceutically acceptable Salt, Solvate, clath in need thereof a therapeutically effective amount of eSZopi rate, polymorph, or co-crystal thereof; a therapeutically clone, or a pharmaceutically acceptable Salt, Solvate, clath effective amount of a 5-HTA modulator, wherein Said rate, polymorph, or co-crystal thereof, and a therapeutically 5-HT modulator is MDL 100907, SR 46349B, YM 992, effective amount of a 5-HTA modulator. fananserin, oxazolidine compounds A, phenylindole com pounds A, piperidinyl compounds B, Spiroazacyclic com 0522. In certain embodiments, the present invention pounds C, azacyclic compounds D, or a pharmaceutically relates to the aforementioned method, wherein the 5-HTA acceptable Salt, Solvate, clathrate, polymorph, or co-crystal modulator is a 5-HT2A antagonist. of any one of them; and at least one pharmaceutically 0523. In certain embodiments, the present invention acceptable carrier. relates to the aforementioned method, wherein the 5-HTA 0532. In certain embodiments, the present invention modulator is a 5-HT, inverse agonist. relates to the aforementioned method, wherein the 5-HT2A 0524. Another aspect of the present invention relates to a modulator is MDL 100907, SR 46349B, YM 992, fan method of treating a patient Suffering from a Sleep abnor anSerin, oxazolidine compounds A, or phenylindole com mality, comprising the Step of co-administering to a patient pounds A, or a pharmaceutically acceptable Salt, Solvate, in need thereof a therapeutically effective amount of eSZopi clathrate, polymorph, or co-crystal of any one of them. clone, or a pharmaceutically acceptable Salt, Solvate, clath 0533. In certain embodiments, the present invention rate, polymorph, or co-crystal thereof, and a therapeutically relates to the aforementioned method, wherein the 5-HT effective amount of a 5-HTA modulator, wherein said modulator is MDL 100907, SR 46349B, YM 992, or fan 5-HT modulator is MDL 100907, SR 46349B, YM 992, anSerin, or a pharmaceutically acceptable Salt, Solvate, clath fananserin, oxazolidine compounds A, phenylindole com pounds A, piperidinyl compounds B, Spiroazacyclic com rate, polymorph, or co-crystal of any one of them. pounds C, azacyclic compounds D, or a pharmaceutically 0534. In certain embodiments, the present invention acceptable Salt, Solvate, clathrate, polymorph, or co-crystal relates to the aforementioned method, wherein the 5-HT of any one of them. modulator is piperidinyl compounds B, Spiroazacyclic com pounds C, azacyclic compounds D, or a pharmaceutically 0525) In certain embodiments, the present invention acceptable Salt, Solvate, clathrate, polymorph, or co-crystal relates to the aforementioned method, wherein the 5-HTA of any one of them. modulator is MDL 100907, SR 46349B, YM 992, fan anSerin, oxazolidine compounds A, or phenylindole com 0535 In certain embodiments, the present invention pounds A, or a pharmaceutically acceptable Salt, Solvate, relates to the aforementioned method, wherein Said Sleep clathrate, polymorph, or co-crystal of any one of them. abnormality is difficulty falling asleep, difficulty staying asleep, or waking up too early. 0526 In certain embodiments, the present invention relates to the aforementioned method, wherein the 5-HTA 0536 Another aspect of the present invention relates to a modulator is MDL 100907, SR 46349B, YM 992, or fan method of treating a patient Suffering from insomnia, com anSerin, or a pharmaceutically acceptable Salt, Solvate, clath prising the Step of co-administering to a patient in need rate, polymorph, or co-crystal of any one of them. thereof a therapeutically effective amount of eSZopiclone, or a pharmaceutically acceptable Salt, Solvate, clathrate, poly 0527. In certain embodiments, the present invention morph, or co-crystal thereof, and a therapeutically effective relates to the aforementioned method, wherein the 5-HT, modulator is piperidinyl compounds B, Spiroazacyclic com amount of a 5-HT2A modulator. pounds C, azacyclic compounds D, or a pharmaceutically 0537. In certain embodiments, the present invention acceptable Salt, Solvate, clathrate, polymorph, or co-crystal relates to the aforementioned method, wherein the 5-HT2A of any one of them. modulator is a 5-HT2A antagonist. US 2005/0176680 A1 Aug. 11, 2005 53

0538 In certain embodiments, the present invention 0547. In certain embodiments, the present invention relates to the aforementioned method, wherein the 5-HTA relates to the aforementioned method, wherein the 5-HT2A modulator is a 5-HT2A inverse agonist. modulator is MDL 100907, SR 46349B, YM 992, fan 0539 Another aspect of the present invention relates to a anSerin, oxazolidine compounds A, or phenylindole com method of treating a patient Suffering from insomnia, com pounds A, or a pharmaceutically acceptable Salt, Solvate, prising the Step of co-administering to a patient in need clathrate, polymorph, or co-crystal of any one of them. thereof a therapeutically effective amount of eSZopiclone, or 0548. In certain embodiments, the present invention a pharmaceutically acceptable Salt, Solvate, clathrate, poly relates to the aforementioned method, wherein the 5-HT2A morph, or co-crystal thereof, and a therapeutically effective modulator is MDL 100907, SR 46349B, YM 992, or fan amount of a 5-HTA modulator, wherein Said 5-HTA modu anSerin, or a pharmaceutically acceptable Salt, Solvate, clath lator is MDL 100907, SR 46349B, YM 992, fananserin, rate, polymorph, or co-crystal of any one of them. Oxazolidine compounds A, phenylindole compounds A, pip eridinyl compounds B, Spiroazacyclic compounds C, aza 0549. In certain embodiments, the present invention cyclic compounds D, or a pharmaceutically acceptable Salt, relates to the aforementioned method, wherein the 5-HT2A Solvate, clathrate, polymorph, or co-crystal of any one of modulator is piperidinyl compounds B, Spiroazacyclic com them. pounds C, azacyclic compounds D, or a pharmaceutically acceptable Salt, Solvate, clathrate, polymorph, or co-crystal 0540. In certain embodiments, the present invention of any one of them. relates to the aforementioned method, wherein the 5-HTA modulator is MDL 100907, SR 46349B, YM 992, fan 0550. In certain embodiments, the present invention anSerin, oxazolidine compounds A, or phenylindole com relates to the aforementioned method, wherein Said insom pounds A, or a pharmaceutically acceptable Salt, Solvate, nia is transient insomnia. clathrate, polymorph, or co-crystal of any one of them. 0551. In certain embodiments, the present invention 0541. In certain embodiments, the present invention relates to the aforementioned method, wherein Said insom relates to the aforementioned method, wherein the 5-HT, nia is short-term insomnia. modulator is MDL 100907, SR 46349B, YM 992, or fan anSerin, or a pharmaceutically acceptable Salt, Solvate, clath 0552. In certain embodiments, the present invention rate, polymorph, or co-crystal of any one of them. relates to the aforementioned method, wherein Said insom nia is chronic insomnia. 0542. In certain embodiments, the present invention relates to the aforementioned method, wherein the 5-HTA 0553 Another aspect of the present invention relates to a modulator is piperidinyl compounds B, Spiroazacyclic com method of treating a patient Suffering from depression, pounds C, azacyclic compounds D, or a pharmaceutically comprising the Step of co-administering to a patient in need acceptable Salt, Solvate, clathrate, polymorph, or co-crystal thereof a therapeutically effective amount of eSZopiclone, or of any one of them. a pharmaceutically acceptable Salt, Solvate, clathrate, poly morph, or co-crystal thereof, and a therapeutically effective 0543. Another aspect of the present invention relates to a amount of a 5-HT2A modulator. method of treating a patient Suffering from insomnia, com prising the Step of co-administering to a patient in need 0554. In certain embodiments, the present invention thereof a therapeutically effective amount of eSZopiclone, or relates to the aforementioned method, wherein the 5-HT a pharmaceutically acceptable Salt, Solvate, clathrate, poly modulator is a 5-HT2A antagonist. morph, or co-crystal thereof; a therapeutically effective 0555. In certain embodiments, the present invention amount of a 5-HT modulator; and at least one pharma relates to the aforementioned method, wherein the 5-HT2A ceutically acceptable carrier. modulator is a 5-HT2A inverse agonist. 0544. In certain embodiments, the present invention 0556. Another aspect of the present invention relates to a relates to the aforementioned method, wherein the 5-HTA method of treating a patient Suffering from depression, modulator is a 5-HT2A antagonist. comprising the Step of co-administering to a patient in need 0545. In certain embodiments, the present invention thereof a therapeutically effective amount of eSZopiclone, or relates to the aforementioned method, wherein the 5-HTA a pharmaceutically acceptable Salt, Solvate, clathrate, poly modulator is a 5-HT, inverse agonist. morph, or co-crystal thereof, and a therapeutically effective amount of a 5-HTA modulator, wherein Said 5-HTA modu 0546) Another aspect of the present invention relates to a lator is MDL 100907, SR 46349B, YM 992, fananserin, method of treating a patient Suffering from insomnia, com Oxazolidine compounds A, phenylindole compounds A, pip prising the Step of co-administering to a patient in need eridinyl compounds B, Spiroazacyclic compounds C, aza thereof a therapeutically effective amount of eSZopiclone, or cyclic compounds D, or a pharmaceutically acceptable Salt, a pharmaceutically acceptable Salt, Solvate, clathrate, poly Solvate, clathrate, polymorph, or co-crystal of any one of morph, or co-crystal thereof; a therapeutically effective them. amount of a 5-HT modulator, wherein said 5-HTA modu lator is MDL 100907, SR 46349B, YM 992, fananserin, 0557. In certain embodiments, the present invention Oxazolidine compounds A, phenylindole compounds A, pip relates to the aforementioned method, wherein the 5-HT eridinyl compounds B, Spiroazacyclic compounds C, aza modulator is MDL 100907, SR 46349B, YM 992, fan cyclic compounds D, or a pharmaceutically acceptable Salt, anSerin, oxazolidine compounds A, or phenylindole com Solvate, clathrate, polymorph, or co-crystal of any one of pounds A, or a pharmaceutically acceptable Salt, Solvate, them; and at least one pharmaceutically acceptable carrier. clathrate, polymorph, or co-crystal of any one of them. US 2005/0176680 A1 Aug. 11, 2005 54

0558. In certain embodiments, the present invention patient comprising administering to the patient in need relates to the aforementioned method, wherein the 5-HTA thereof, undergoing antidepressant therapy, a therapeutically modulator is MDL 100907, SR 46349B, YM 992, or fan effective amount of eSZopiclone, or a pharmaceutically anSerin, or a pharmaceutically acceptable Salt, Solvate, clath acceptable Salt, Solvate, clathrate, polymorph, or co-crystal rate, polymorph, or co-crystal of any one of them. thereof. 0559). In certain embodiments, the present invention 0569. Another aspect of the present invention relates to a relates to the aforementioned method, wherein the 5-HTA method for eliciting a dose sparing effect in a patient modulator is piperidinyl compounds B, Spiroazacyclic com undergoing treatment with an antidepressant, comprising pounds C, azacyclic compounds D, or a pharmaceutically administering to the patient in need thereof, undergoing acceptable Salt, Solvate, clathrate, polymorph, or co-crystal antidepressant therapy, a therapeutically effective amount of of any one of them. eSZopiclone, or a pharmaceutically acceptable Salt, Solvate, 0560 Another aspect of the present invention relates to a clathrate, polymorph, or co-crystal thereof. method of treating a patient Suffering from depression, 0570 Another aspect of the present invention relates to a comprising the Step of co-administering to a patient in need method for reducing depression relapse in a patient who thereof a therapeutically effective amount of eSZopiclone, or received antidepressant treatment, comprising administering a pharmaceutically acceptable Salt, Solvate, clathrate, poly to the patient in need thereof a therapeutically effective morph, or co-crystal thereof; a therapeutically effective amount of eSZopiclone, or a pharmaceutically acceptable amount of a 5-HTA modulator, and at least one pharma Salt, Solvate, clathrate, polymorph, or co-crystal thereof. ceutically acceptable carrier. 0571. In certain embodiments, the present invention 0561. In certain embodiments, the present invention relates to the aforementioned method, wherein the eSZopi relates to the aforementioned method, wherein the 5-HT, clone is administered chronically or long-term. modulator is a 5-HT2A antagonist. 0572 Another aspect of the present invention relates to a 0562. In certain embodiments, the present invention method for improving the tolerability of antidepressant relates to the aforementioned method, wherein the 5-HTA therapy in a patient Suffering from depression, comprising modulator is a 5-HT, inverse agonist. administering to the patient in need thereof, undergoing 0563 Another aspect of the present invention relates to a antidepressant therapy, a therapeutically effective amount of method of treating a patient Suffering from depression, eSzopiclone, or a pharmaceutically acceptable Salt, Solvate, comprising the Step of co-administering to a patient in need clathrate, polymorph, or co-crystal thereof. thereof a therapeutically effective amount of eSZopiclone, or 0573. In certain embodiments, the present invention a pharmaceutically acceptable Salt, Solvate, clathrate, poly relates to the aforementioned method, wherein the antide morph, or co-crystal thereof; a therapeutically effective preSSant is citalopram, dulloxetine, escitalopram, fluoxetine, amount of a 5-HTA modulator, wherein Said 5-HTA modu fluvoxamine, milnacipran, paroxetine, Sertraline, clomin lator is MDL 100907, SR 46349B, YM 992, fananserin, Oxazolidine compounds A, phenylindole compounds A, pip pramine, femoxetine, indapline, alaprolclate, cericlamine, eridinyl compounds B, Spiroazacyclic compounds C, aza ifoxetine, or a pharmaceutically acceptable Salt, Solvate, cyclic compounds D, or a pharmaceutically acceptable Salt, clathrate, polymorph, or co-crystal of any one of them. Solvate, clathrate, polymorph, or co-crystal of any one of 0574. In certain embodiments, the present invention them; and at least one pharmaceutically acceptable carrier. relates to the aforementioned method, wherein the antide 0564) In certain embodiments, the present invention preSSant is desipramine, maprotiline, lofepramine, reboxet relates to the aforementioned method, wherein the 5-HT, ine, Oxaprotiline, fezolamine, tomoxetine, (S,S) hydroxybu modulator is MDL 100907, SR 46349B, YM 992, fan propion, or a pharmaceutically acceptable Salt, Solvate, anSerin, oxazolidine compounds A, or phenylindole com clathrate, polymorph, or co-crystal of any one of them. pounds A, or a pharmaceutically acceptable Salt, Solvate, 0575. In certain embodiments, the present invention clathrate, polymorph, or co-crystal of any one of them. relates to the aforementioned method, wherein the antide 0565. In certain embodiments, the present invention preSSant is bupropion, Venlafaxine, or desmethylvenlafax relates to the aforementioned method, wherein the 5-HTA ine, or a pharmaceutically acceptable Salt, Solvate, clathrate, modulator is MDL 100907, SR 46349B, YM 992, or fan polymorph, or co-crystal of any one of them. anSerin, or a pharmaceutically acceptable Salt, Solvate, clath 0576. In certain embodiments, the present invention rate, polymorph, or co-crystal of any one of them. relates to the aforementioned method, wherein the desmeth 0566 In certain embodiments, the present invention ylvenlafaxine is racemic desmethylvenlafaxine, (+)-desm relates to the aforementioned method, wherein the 5-HTA ethylvenlafaxine, or (-)-desmethylvenlafaxine, or a pharma modulator is piperidinyl compounds B, Spiroazacyclic com ceutically acceptable Salt, Solvate, clathrate, polymorph, or pounds C, azacyclic compounds D, or a pharmaceutically co-crystal of any one of them. acceptable Salt, Solvate, clathrate, polymorph, or co-crystal 0577. In certain embodiments, the present invention of any one of them. relates to the aforementioned method, wherein the antide 0567. In certain embodiments, the present invention preSSant is a dopamine reuptake inhibitor or an atypical relates to the aforementioned method, wherein Said depres antidepressant. Sion is a major depressive disorder. 0578. One aspect of the present invention relates to a 0568 Another aspect of the present invention relates to a pharmaceutical composition, comprising a Sedative agent method for augmentation of antidepressant therapy in a and an antidepressant. In certain embodiments, the antide US 2005/0176680 A1 Aug. 11, 2005 55 preSSant is a Serotonin reuptake inhibitor, including without 0587 Another aspect of the present invention relates to a limitation Selective Serotonin reuptake inhibitors, a norepi pharmaceutical composition, comprising a Sedative agent nephrine reuptake inhibitor, including without limitation a and a Serotonin reuptake inhibitor; wherein Said Sedative Selective norepinephrine reuptake inhibitor, a dopamine agent is racemic Zopiclone, eSZopiclone, or a pharmaceuti reuptake inhibitor, or an atypical antidepressant. In other cally acceptable Salt, Solvate, clathrate, polymorph, or co embodiments, the antidepressant is citalopram, dulloxetine, crystal of either of them; and Said Serotonin reuptake inhibi escitalopram, fluoxetine, fluvoxamine, milnacipran, paroX tor is fluoxetine, paroxetine, or a pharmaceutically etine, Sertraline, clominpramine, femoxetine, indapline, ala acceptable Salt, Solvate, clathrate, polymorph, or co-crystal prolclate, cericlamine, ifoxetine, or a pharmaceutically of either of them. acceptable Salt, Solvate, clathrate, polymorph, or co-crystal 0588 Another aspect of the present invention relates to a of any one of them. pharmaceutical composition, comprising a Sedative agent 0579. Another aspect of the present invention relates to a and a Serotonin reuptake inhibitor; wherein Said Sedative pharmaceutical composition, comprising a Sedative agent agent is eSZopiclone or a pharmaceutically acceptable Salt, and a Serotonin reuptake inhibitor; wherein Said Sedative Solvate, clathrate, polymorph, or co-crystal thereof, and Said agent is a compound that modulates the activity of a GABA Serotonin reuptake inhibitor is fluoxetine or a pharmaceuti receptor and has a K, less than about 300 nM in a GABA cally acceptable Salt, Solvate, clathrate, polymorph, or co receptor binding assay; and Said Serotonin reuptake inhibitor crystal thereof. is citalopram, dulloxetine, escitalopram, fluoxetine, fluvox 0589 Another aspect of the present invention relates to a amine, milnacipran, paroxetine, Sertraline, clominpramine, pharmaceutical composition, comprising eSZopiclone or a femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, pharmaceutically acceptable Salt, Solvate, clathrate, poly or a pharmaceutically acceptable Salt, Solvate, clathrate, morph, or co-crystal thereof and fluoxetine hydrochloride or polymorph, or co-crystal of any one of them. a pharmaceutically acceptable Salt, Solvate, clathrate, poly 0580. In certain embodiments, the present invention morph, or co-crystal thereof. relates to the aforementioned pharmaceutical composition, 0590 Another aspect of the present invention relates to a wherein said K is less than about 150 nM. pharmaceutical composition, comprising a Sedative agent and a norepinephrine reuptake inhibitor; wherein Said Seda 0581. In certain embodiments, the present invention tive agent is a compound that modulates the activity of a relates to the aforementioned pharmaceutical composition, GABA receptor and has a K, less than about 300 nM in a wherein said K is less than about 75 nM. GABA-receptor binding assay; and Said norepinephrine 0582. In certain embodiments, the present invention reuptake inhibitor is desipramine, maprotiline, lofepramine, relates to the aforementioned pharmaceutical composition, reboxetine, Oxaprotiline, fezolamine, tomoxetine, (S,S)-hy wherein said K is less than about 30 nM. droxybupropion, or a pharmaceutically acceptable Salt, Sol Vate, clathrate, polymorph, or co-crystal of any one of them. 0583. Another aspect of the present invention relates to a pharmaceutical composition, comprising a Sedative agent 0591. In certain embodiments, the present invention and a Serotonin reuptake inhibitor; wherein Said Sedative relates to the aforementioned pharmaceutical composition, agent is racemic Zopiclone, eSZopiclone, indiplon, Zolpidem, wherein said K is less than about 150 nM. Zaleplon, gabOXadol, or a pharmaceutically acceptable Salt, 0592. In certain embodiments, the present invention Solvate, clathrate, polymorph, or co-crystal of any one of relates to the aforementioned pharmaceutical composition, them; and Said Serotonin reuptake inhibitor is citalopram, wherein said K is less than about 75 nM. dulloxetine, escitalopram, fluoxetine, fluvoxamine, milnacip ran, paroxetine, Sertraline, clominpramine, femoxetine, 0593. In certain embodiments, the present invention indapline, alaprolclate, cericlamine, ifoxetine, or a pharma relates to the aforementioned pharmaceutical composition, ceutically acceptable Salt, Solvate, clathrate, polymorph, or wherein said K is less than about 30 nM. co-crystal of any one of them. 0594. Another aspect of the present invention relates to a 0584) In certain embodiments, the present invention pharmaceutical composition, comprising a Sedative agent relates to the aforementioned pharmaceutical composition, and a norepinephrine reuptake inhibitor; wherein Said Seda wherein Said Sedative agent is racemic Zopiclone, eSZopi tive agent is racemic Zopiclone, eSZopiclone, indiplon, Zolpi clone, indiplon, or a pharmaceutically acceptable Salt, Sol dem, Zaleplon, gaboXadol, or a pharmaceutically acceptable Vate, clathrate, polymorph, or co-crystal of any one of them. Salt, Solvate, clathrate, polymorph, or co-crystal of any one of them; and Said norepinephrine reuptake inhibitor is 0585. In certain embodiments, the present invention desipramine, maprotiline, lofepramine, reboxetine, Oxapro relates to the aforementioned pharmaceutical composition, tiline, feZolamine, tomoxetine, (S,S)-hydroxybupropion, or wherein Said Sedative agent is eSZopiclone, or a pharmaceu a pharmaceutically acceptable Salt, Solvate, clathrate, poly tically acceptable Salt, Solvate, clathrate, polymorph, or morph, or co-crystal of any one of them. co-crystal thereof. 0595 Another aspect of the present invention relates to a 0586. In certain embodiments, the present invention pharmaceutical composition, comprising a Sedative agent relates to the aforementioned pharmaceutical composition, and a norepinephrine reuptake inhibitor; wherein Said Seda wherein Said Serotonin reuptake inhibitor is fluoxetine, flu tive agent is eSZopiclone or a pharmaceutically acceptable Voxamine, milnacipran, paroxetine, or a pharmaceutically Salt, Solvate, clathrate, polymorph, or co-crystal thereof, and acceptable Salt, Solvate, clathrate, polymorph, or co-crystal Said norepinephrine reuptake inhibitor is desipramine, of any one of them. maprotiline, lofepramine, reboxetine, Oxaprotiline, feZola US 2005/0176680 A1 Aug. 11, 2005 56 mine, tomoxetine, (S,S)-hydroxybupropion, or a pharma anSerin, oxazolidine compounds A, phenylindole com ceutically acceptable Salt, Solvate, clathrate, polymorph, or pounds A, piperidinyl compounds B, Spiroazacyclic com co-crystal of any one of them. pounds C, azacyclic compounds D, or a pharmaceutically 0596) In certain embodiments, the present invention acceptable Salt, Solvate, clathrate, polymorph, or co-crystal relates to the aforementioned pharmaceutical composition, of any one of them. wherein Said norepinephrine reuptake inhibitor is 0605. In certain embodiments, the present invention desipramine, reboxetine, Oxaprotiline, (S,S)-hydroxybupro relates to the aforementioned pharmaceutical composition, pion, or a pharmaceutically acceptable Salt, Solvate, clath wherein said 5-HT, modulator is MDL 100907, SR rate, polymorph, or co-crystal of any one of them. 46349B, YM 992, fananserin, or a pharmaceutically accept 0597 Another aspect of the present invention relates to a able Salt, Solvate, clathrate, polymorph, or co-crystal of any pharmaceutical composition, comprising eSZopiclone or a one of them. pharmaceutically acceptable Salt, Solvate, clathrate, poly 0606 Another aspect of the present invention relates to a morph, or co-crystal thereof, and a norepinephrine reuptake pharmaceutical composition, comprising eSZopiclone and a inhibitor; wherein Said norepinephrine reuptake inhibitor is 5-HTA modulator; wherein said 5-HT modulator is MDL desipramine, reboxetine, Oxaprotiline, (S,S)-hydroxybupro 100907, SR 46349B, YM 992, fananserin, or a pharmaceu pion, or a pharmaceutically acceptable Salt, Solvate, clath tically acceptable Salt, Solvate, clathrate, polymorph, or rate, polymorph, or co-crystal of any one of them. co-crystal of any one of them. 0598. Another aspect of the present invention relates to a 0607 Another aspect of the present invention relates to a pharmaceutical composition, comprising a Sedative agent pharmaceutical composition, comprising eSZopiclone, or a and a 5-HT, receptor modulator. In certain embodiments, the pharmaceutically acceptable Salt, Solvate, clathrate, poly 5-HT, receptor modulator is a 5-HT, receptor antagonist or morph, or co-crystal thereof, and a 5-HT, inverse agonist. a 5-HTA inverse agonist. In certain embodiments, the 5-HT2A inverse agonist is pip 0599. In one embodiment, the pharmaceutical composi eridinyl compounds B, Spiroazacyclic compounds C, aza tion comprises a Sedative agent and a 5-HT2 receptor modu cyclic compounds D, or a pharmaceutically acceptable Salt, lator, wherein Said Sedative agent is a compound that modu Solvate, clathrate, polymorph, or co-crystal of any one of lates the activity of a GABA receptor and has a KleSS than them about 300 nM in a GABA-receptor binding assay; and said 0608 Another aspect of the present invention relates to a said 5-HT, receptor modulator is MDL 100907, SR 46349B, pharmaceutical composition, comprising a Sedative agent YM 992, fananserin, oxazolidine compounds A, phenylin and a dopamine reuptake inhibitor; wherein Said Sedative dole compounds A, piperidinyl compounds B, SpiroaZacy agent is a compound that modulates the activity of a GABA clic compounds C, azacyclic compounds D, or a pharma receptor and has a K, less than about 300 nM in a GABA ceutically acceptable Salt, Solvate, clathrate, polymorph, or receptor binding assay; and Said dopamine reuptake inhibi co-crystal of any one of them. tor is amineptine, bupropion, GBR-12935, venlafaxine, 0600. In certain embodiments, the present invention 2?-propanoyl-3?-(4-tolyl)-tropane, or a pharmaceutically relates to the aforementioned pharmaceutical composition, acceptable Salt, Solvate, clathrate, polymorph, or co-crystal wherein said K is less than about 150 nM. of any one of them. 0601. In certain embodiments, the present invention 0609. In certain embodiments, the present invention relates to the aforementioned pharmaceutical composition, relates to the aforementioned pharmaceutical composition, wherein said K is less than about 75 nM. wherein said K is less than about 150 nM. 0602. In certain embodiments, the present invention 0610. In certain embodiments, the present invention relates to the aforementioned pharmaceutical composition, relates to the aforementioned pharmaceutical composition, wherein said K is less than about 30 nM.; wherein said K is less than about 75 nM. 0603 Another aspect of the present invention relates to a 0611. In certain embodiments, the present invention pharmaceutical composition, comprising a Sedative agent relates to the aforementioned pharmaceutical composition, and a 5-HT modulator; wherein said Sedative agent is wherein said K is less than about 30 nM. racemic Zopiclone, eSZopiclone, indiplon, Zolpidem, Zale 0612 Another aspect of the present invention relates to a plon, gaboxadol, or a pharmaceutically acceptable Salt, pharmaceutical composition, comprising a Sedative agent Solvate, clathrate, polymorph, or co-crystal of any one of and a dopamine reuptake inhibitor; wherein Said Sedative them; and said 5-HT modulator is MDL 100907, SR agent is racemic Zopiclone, eSZopiclone, indiplon, Zolpidem, 46349B, YM 992, fananserin, oxazolidine compounds A, Zaleplon, gaboxadol, or a pharmaceutically acceptable Salt, phenylindole compounds A, piperidinyl compounds B, Solvate, clathrate, polymorph, or co-crystal of any one of Spiroazacyclic compounds C, azacyclic compounds D, or a them; and Said dopamine reuptake inhibitor is amineptine, pharmaceutically acceptable Salt, Solvate, clathrate, poly bupropion, GBR-12935, venlafaxine, 2B-propanoyl-3?-(4- morph, or co-crystal of any one of them. tolyl)-tropane, or a pharmaceutically acceptable Salt, Sol 0604. Another aspect of the present invention relates to a Vate, clathrate, polymorph, or co-crystal of any one of them. pharmaceutical composition, comprising a Sedative agent 0613 Another aspect of the present invention relates to a and a 5-HTA modulator; wherein Said Sedative agent is pharmaceutical composition, comprising a Sedative agent eSZopiclone or a pharmaceutically acceptable Salt, Solvate, and a dopamine reuptake inhibitor; wherein Said Sedative clathrate, polymorph, or co-crystal thereof, and Said 5-HTA agent is eSZopiclone or a pharmaceutically acceptable Salt, modulator is MDL 100907, SR 46349B, YM 992, fan Solvate, clathrate, polymorph, or co-crystal thereof, and Said US 2005/0176680 A1 Aug. 11, 2005 57 dopamine reuptake inhibitor is amineptine, bupropion, Sedative agent, a Serotonin reuptake inhibitor, and at least GBR-12935, venlafaxine, 2B-propanoyl-3?-(4-tolyl)-tro one pharmaceutically acceptable carrier; wherein Said Seda pane, or a pharmaceutically acceptable Salt, Solvate, clath tive agent is racemic Zopiclone, eSZopiclone, or a pharma rate, polymorph, or co-crystal of any one of them. ceutically acceptable Salt, Solvate, clathrate, polymorph, or 0614. In certain embodiments, the present invention co-crystal of either of them; and Said Serotonin reuptake relates to the aforementioned pharmaceutical composition, inhibitor is fluoxetine, paroxetine, or a pharmaceutically wherein Said dopamine reuptake inhibitor is bupropion, acceptable Salt, Solvate, clathrate, polymorph, or co-crystal GBR-12935, or a pharmaceutically acceptable salt, Solvate, of either of them. clathrate, polymorph, or co-crystal of either of them. 0624. Another aspect of the present invention relates to a 0615. Another aspect of the present invention relates to a pharmaceutical composition, consisting essentially of a pharmaceutical composition, comprising eSZopiclone and Sedative agent, a Serotonin reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein Said Seda bupropion, or a pharmaceutically acceptable Salt, Solvate, tive agent is eSZopiclone or a pharmaceutically acceptable clathrate, polymorph, or co-crystal of either of them. Salt, Solvate, clathrate, polymorph, or co-crystal thereof, and 0616) Another aspect of the present invention relates to a Said Serotonin reuptake inhibitor is fluoxetine or a pharma pharmaceutical composition, consisting essentially of a ceutically acceptable Salt, Solvate, clathrate, polymorph, or Sedative agent, a Serotonin reuptake inhibitor, and at least co-crystal thereof. one pharmaceutically acceptable carrier; wherein Said Seda tive agent is a compound that modulates the activity of a 0625) Another aspect of the present invention relates to a GABA receptor and has a K, less than about 300 nM in a pharmaceutical composition, consisting essentially of GABA-receptor binding assay; and Said Serotonin reuptake eSZopiclone or a pharmaceutically acceptable Salt, Solvate, inhibitor is citalopram, dulloxetine, escitalopram, fluoxetine, clathrate, polymorph, or co-crystal thereof, fluoxetine fluvoxamine, milnacipran, paroxetine, Sertraline, clomin hydrochloride or a pharmaceutically acceptable Salt, Solvate, pramine, femoxetine, indapline, alaprolclate, cericlamine, clathrate, polymorph, or co-crystal therof, and at least one ifoxetine, or a pharmaceutically acceptable Salt, Solvate, pharmaceutically acceptable carrier. clathrate, polymorph, or co-crystal of any one of them. 0626. Another aspect of the present invention relates to a 0617. In certain embodiments, the present invention pharmaceutical composition, consisting essentially of a relates to the aforementioned pharmaceutical composition, Sedative agent, a norepinephrine reuptake inhibitor, and at wherein said K is less than about 150 nM. least one pharmaceutically acceptable carrier; wherein said Sedative agent is a compound that modulates the activity of 0618. In certain embodiments, the present invention a GABA receptor and has a K, less than about 300 nM in a relates to the aforementioned pharmaceutical composition, GABA-receptor binding assay; and Said norepinephrine wherein said K is less than about 75 nM. reuptake inhibitor is desipramine, maprotiline, lofepramine, 0619. In certain embodiments, the present invention reboxetine, Oxaprotiline, fezolamine, tomoxetine, (S,S)-hy relates to the aforementioned pharmaceutical composition, droxybupropion, or a pharmaceutically acceptable Salt, Sol wherein said K is less than about 30 nM. Vate, clathrate, polymorph, or co-crystal of any one of them. 0620. Another aspect of the present invention relates to a 0627. In certain embodiments, the present invention pharmaceutical composition, consisting essentially of a relates to the aforementioned pharmaceutical composition, Sedative agent, a Serotonin reuptake inhibitor, and at least wherein said K is less than about 150 nM. one pharmaceutically acceptable carrier; wherein Said Seda tive agent is racemic Zopiclone, eSZopiclone, indiplon, Zolpi 0628. In certain embodiments, the present invention dem, Zaleplon, gaboXadol, or a pharmaceutically acceptable relates to the aforementioned pharmaceutical composition, Salt, Solvate, clathrate, polymorph, or co-crystal of any one wherein said K is less than about 75 nM. of them; and Said Serotonin reuptake inhibitor is citalopram, 0629. In certain embodiments, the present invention dulloxetine, escitalopram, fluoxetine, fluvoxamine, milnacip relates to the aforementioned pharmaceutical composition, ran, paroxetine, Sertraline, clominpramine, femoxetine, wherein said K is less than about 30 nM. indapline, alaprolclate, cericlamine, ifoxetine, or a pharma ceutically acceptable Salt, Solvate, clathrate, polymorph, or 0630. Another aspect of the present invention relates to a co-crystal of any one of them. pharmaceutical composition, consisting essentially of a Sedative agent, a norepinephrine reuptake inhibitor, and at 0621. In certain embodiments, the present invention least one pharmaceutically acceptable carrier, wherein Said relates to the aforementioned pharmaceutical composition, Sedative agent is racemic Zopiclone, eSZopiclone, indiplon, wherein Said Sedative agent is racemic Zopiclone, eSZopi Zolpidem, Zaleplon, gaboxadol, or a pharmaceutically clone, indiplon, or a pharmaceutically acceptable Salt, Sol acceptable Salt, Solvate, clathrate, polymorph, or co-crystal Vate, clathrate, polymorph, or co-crystal of any one of them. of any one of them; and Said norepinephrine reuptake 0622. In certain embodiments, the present invention inhibitor is desipramine, maprotiline, lofepramine, reboxet relates to the aforementioned pharmaceutical composition, ine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybu wherein Said Serotonin reuptake inhibitor is fluoxetine, flu propion, or a pharmaceutically acceptable Salt, Solvate, Voxamine, milnacipran, paroxetine, or a pharmaceutically clathrate, polymorph, or co-crystal of any one of them. acceptable Salt, Solvate, clathrate, polymorph, or co-crystal 0631 Another aspect of the present invention relates to a of any one of them. pharmaceutical composition, consisting essentially of a 0623) Another aspect of the present invention relates to a Sedative agent, a norepinephrine reuptake inhibitor, and at pharmaceutical composition, consisting essentially of a least one pharmaceutically acceptable carrier; wherein Said US 2005/0176680 A1 Aug. 11, 2005 58

Sedative agent is eSZopiclone or a pharmaceutically accept is eSZopiclone or a pharmaceutically acceptable Salt, Solvate, able Salt, Solvate, clathrate, polymorph, or co-crystal thereof; clathrate, polymorph, or co-crystal thereof; and Said 5-HT2A and Said norepinephrine reuptake inhibitor is desipramine, modulator is MDL 100907, SR 46349B, YM 992, fan maprotiline, lofepramine, reboxetine, Oxaprotiline, feZola anSerin, oxazolidine compounds A, phenylindole com mine, tomoxetine, (S,S)-hydroxybupropion, or a pharma pounds A, piperidinyl compounds B, Spiroazacyclic com ceutically acceptable Salt, Solvate, clathrate, polymorph, or pounds C, azacyclic compounds D, or a pharmaceutically co-crystal of any one of them. acceptable Salt, Solvate, clathrate, polymorph, or co-crystal 0632. In certain embodiments, the present invention of any one of them. relates to the aforementioned pharmaceutical composition, 0.640. In certain embodiments, the present invention wherein Said norepinephrine reuptake inhibitor is relates to the aforementioned pharmaceutical composition, desipramine, reboxetine, Oxaprotiline, (S,S)-hydroxybupro wherein said 5-HT, modulator is MDL 100907, SR pion, or a pharmaceutically acceptable Salt, Solvate, clath 46349B, YM 992, fananserin, or a pharmaceutically accept rate, polymorph, or co-crystal of any one of them. able Salt, Solvate, clathrate, polymorph, or co-crystal of any 0633) Another aspect of the present invention relates to a one of them. pharmaceutical composition, consisting essentially of 0641 Another aspect of the present invention relates to a eSZopiclone or a pharmaceutically acceptable Salt, Solvate, pharmaceutical composition, consisting essentially of clathrate, polymorph, or co-crystal thereof, a norepinephrine eSZopiclone, or a pharmaceutically acceptable Salt, Solvate, reuptake inhibitor, and at least one pharmaceutically accept clathrate, polymorph, or co-crystal of any one of them, a able carrier; wherein Said norepinephrine reuptake inhibitor 5-HT modulator, and at least one pharmaceutically accept is desipramine, reboxetine, Oxaprotiline, (S,S)-hydroxybu able carrier; wherein said 5-HT modulator is MDL propion, or a pharmaceutically acceptable Salt, Solvate, 100907, SR 46349B, YM 992, fananserin, or a pharmaceu clathrate, polymorph, or co-crystal of any one of them. tically acceptable Salt, Solvate, clathrate, polymorph, or 0634. Another aspect of the present invention relates to a co-crystal of any one of them. pharmaceutical composition, consisting essentially of a 0642 Another aspect of the present invention relates to a Sedative agent, a 5-HTA modulator, and at least one phar pharmaceutical composition, consisting essentially of a maceutically acceptable carrier; wherein Said Sedative agent Sedative agent, a dopamine reuptake inhibitor, and at least is a compound that modulates the activity of a GABA one pharmaceutically acceptable carrier; wherein Said Seda receptor and has a K, less than about 300 nM in a GABA tive agent is a compound that modulates the activity of a receptor binding assay; and said 5-HT modulator is MDL GABA receptor and has a K, less than about 300 nM in a 100907, SR 46349B, YM 992, fananserin, oxazolidine com GABA-receptor binding assay; and Said dopamine reuptake pounds A, phenylindole compounds A, piperidinyl com inhibitor is amineptine, bupropion, GBR-12935, venlafax pounds B, Spiroazacyclic compounds C, azacyclic com ine, 2(3-propanoyl-3?-(4-tolyl)-tropane, or a pharmaceuti pounds D, or a pharmaceutically acceptable Salt, Solvate, cally acceptable Salt, Solvate, clathrate, polymorph, or co clathrate, polymorph, or co-crystal of any one of them. crystal-of any one of them. 0635. In certain embodiments, the present invention 0.643. In certain embodiments, the present invention relates to the aforementioned pharmaceutical composition, relates to the aforementioned pharmaceutical composition, wherein said K is less than about 150 nM. wherein said K is less than about 150 nM. 0636. In certain embodiments, the present invention 0644. In certain embodiments, the present invention relates to the aforementioned pharmaceutical composition, relates to the aforementioned pharmaceutical composition, wherein said K is less than about 75 nM. wherein said K is less than about 75 nM. 0637. In certain embodiments, the present invention 0.645. In certain embodiments, the present invention relates to the aforementioned pharmaceutical composition, relates to the aforementioned pharmaceutical composition, wherein said K is less than about 30 nM. wherein said K is less than about 30 nM. 0638 Another aspect of the present invention relates to a 0646) Another aspect of the present invention relates to a pharmaceutical composition, consisting essentially of a pharmaceutical composition, consisting essentially of a Sedative agent, a 5-HTA modulator, and at least one phar Sedative agent, a dopamine reuptake inhibitor, and at least maceutically acceptable carrier; wherein Said Sedative agent one pharmaceutically acceptable carrier; wherein Said Seda is racemic Zopiclone, eSZopiclone, indiplon, Zolpidem, Zale tive agent is racemic Zopiclone, eSZopiclone, indiplon, Zolpi plon, gaboxadol, or a pharmaceutically acceptable Salt, dem, Zaleplon, gaboXadol, or a pharmaceutically acceptable Solvate, clathrate, polymorph, or co-crystal of any one of Salt, Solvate, clathrate, polymorph, or co-crystal of any one them; and said 5-HT modulator is MDL 100907, SR of them; and Said dopamine reuptake inhibitor is amineptine, 46349B, YM 992, fananserin, oxazolidine compounds A, bupropion, GBR-12935, venlafaxine, 2B-propanoyl-3?-(4- phenylindole compounds A, piperidinyl compounds B, tolyl)-tropane, or a pharmaceutically acceptable Salt, Sol Spiroazacyclic compounds C, azacyclic compounds D, or a Vate, clathrate, polymorph, or co-crystal of any one of them. pharmaceutically acceptable Salt, Solvate, clathrate, poly 0647. Another aspect of the present invention relates to a morph, or co-crystal of any one of them. pharmaceutical composition, consisting essentially of a 0639 Another aspect of the present invention relates to a Sedative agent, a dopamine reuptake inhibitor, and at least pharmaceutical composition, consisting essentially of a one pharmaceutically acceptable carrier; wherein Said Seda Sedative agent, a 5-HTA modulator, and at least one phar tive agent is eSZopiclone or a pharmaceutically acceptable maceutically acceptable carrier; wherein Said Sedative agent Salt, Solvate, clathrate, polymorph, or co-crystal thereof, and US 2005/0176680 A1 Aug. 11, 2005 59

Said dopamine reuptake inhibitor is amineptine, bupropion, Sedative agent and a therapeutically effective amount of a GBR-12935, venlafaxine, 2B-propanoyl-3?-(4-tolyl)-tro Serotonin reuptake inhibitor, wherein Said Sedative agent is pane, or a pharmaceutically acceptable Salt, Solvate, clath racemic Zopiclone, eSZopiclone, indiplon, Zolpidem, Zale rate, polymorph, or co-crystal of any one of them. plon, gaboxadol, or a pharmaceutically acceptable Salt, Solvate, clathrate, polymorph, or co-crystal of any one of 0648. In certain embodiments, the present invention them; and Said Serotonin reuptake inhibitor is citalopram, relates to the aforementioned pharmaceutical composition, dulloxetine, escitalopram, fluoxetine, fluvoxamine, milnacip wherein Said dopamine reuptake inhibitor is bupropion, ran, paroxetine, Sertraline, clominpramine, femoxetine, GBR-12935, or a pharmaceutically acceptable salt, Solvate, indapline, alaprolclate, cericlamine, ifoxetine, or a pharma clathrate, polymorph, or co-crystal of either of them. ceutically acceptable Salt, Solvate, clathrate, polymorph, or 0649. Another aspect of the present invention relates to a co-crystal of any one of them. pharmaceutical composition, consisting essentially of 0654) Another aspect of the present invention relates to a eSZopiclone and bupropion, or a pharmaceutically accept method of treating a patient Suffering from a Sleep abnor able Salt, Solvate, clathrate, polymorph, or co-crystal of mality, comprising the Step of co-administering to a patient either of them, and at least one pharmaceutically acceptable in need thereof a therapeutically effective amount of a carrier. Sedative agent and a therapeutically effective amount of a 0650 Another aspect of the present invention relates to a Serotonin reuptake inhibitor, wherein Said Sedative agent is method of treating a patient Suffering from a Sleep abnor racemic Zopiclone, eSZopiclone, or a pharmaceutically mality, comprising the Step of co-administering to a patient acceptable Salt, Solvate, clathrate, polymorph, or co-crystal in need thereof a therapeutically effective amount of a of either of them; and Said Serotonin reuptake inhibitor is Sedative and a therapeutically effective amount of an anti fluoxetine, paroxetine, or a pharmaceutically acceptable Salt, depressant, wherein Said Sedative agent is a compound that Solvate, clathrate, polymorph, or co-crystal of either of them. modulates the activity of a GABA receptor and has a Kless 0655 Another aspect of the present invention relates to a than about 300 nM in a GABA-receptor binding assay; and method of treating a patient Suffering from a Sleep abnor Said antidepressant is a Serotonin reuptake inhibitor, nore mality, comprising the Step of co-administering to a patient pinephrine reuptake inhibitor, 5HT modulator, or dopam in need thereof a therapeutically effective amount of a ine reuptake inhibitor. Sedative agent and a therapeutically effective amount of a 0651. In certain embodiments, the present invention Serotonin reuptake inhibitor, wherein Said Sedative agent is relates to the aforementioned method, wherein Said Sedative eSZopiclone or a pharmaceutically acceptable Salt, Solvate, is racemic Zopiclone, (S)-Zopiclone, indiplon, Zolpidem, clathrate, polymorph, or co-crystal thereof, and Said Seroto Zaleplon, gabOXadol, or a pharmaceutically acceptable Salt, nin reuptake inhibitor is fluoxetine or a pharmaceutically Solvate, or hydrate of any one of them; and Said antidepres acceptable Salt, Solvate, clathrate, polymorph, or co-crystal Sant is citalopram, dulloxetine, escitalopram, fluoxetine, flu thereof. Voxamine, milnacipran, paroxetine, Sertraline, clomin 0656. Another aspect of the present invention relates to a pramine, femoxetine, indapline, alaprolclate, cericlamine, method of treating a patient Suffering from a Sleep abnor ifoxetine, desipramine, maprotiline, lofepramine, reboxet mality, comprising the Step of co-administering to a patient ine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybu in need thereof a therapeutically effective amount of eSZopi propion, MDL 100907, SR 46349B, YM 992, fananserin, clone or a pharmaceutically acceptable Salt, Solvate, clath Oxazolidine compounds A, phenylindole compounds A, pip rate, polymorph, or co-crystal thereof, and a therapeutically eridinyl compounds B, Spiroazacyclic compounds C, aza effective amount of fluoxetine hydrochloride or a pharma cyclic compounds D, amineptine, bupropion, GBR-12935, ceutically acceptable Salt, Solvate, clathrate, polymorph, or Venlafaxine, or 2,3-propanoyl-3B-(4-tolyl)-tropane, or a co-crystal thereof. pharmaceutically acceptable Salt, Solvate, or hydrate of any one of them. 0657 Another aspect of the present invention relates to a method of treating a patient Suffering from a Sleep abnor 0652) Another aspect of the present invention relates to a mality, comprising the Step of co-administering to a patient method of treating a patient Suffering from a Sleep abnor in need thereof a therapeutically effective amount of a mality, comprising the Step of co-administering to a patient Sedative agent and a therapeutically effective amount of a in need thereof a therapeutically effective amount of a norepinephrine reuptake inhibitor; wherein Said Sedative Sedative agent and a therapeutically effective amount of a agent is a compound that modulates the activity of a GABA Serotonin reuptake inhibitor, wherein Said Sedative agent is receptor and has a K, less than about 300 nM in a GABA a compound that modulates the activity of a GABA receptor receptor binding assay; and Said norepinephrine reuptake and has a K, less than about 300 nM in a GABA-receptor inhibitor is desipramine, maprotiline, lofepramine, reboxet binding assay, and Said Serotonin reuptake inhibitor is ine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybu citalopram, dulloxetine, escitalopram, fluoxetine, fluvoxam propion, or a pharmaceutically acceptable Salt, Solvate, ine, milnacipran, paroxetine, Sertraline, clominpramine, clathrate, polymorph, or co-crystal of any one of them. femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, 0658 Another aspect of the present invention relates to a or a pharmaceutically acceptable Salt, Solvate, clathrate, method of treating a patient Suffering from a Sleep abnor polymorph, or co-crystal of any one of them. mality, comprising the Step of co-administering to a patient 0653 Another aspect of the present invention relates to a in need thereof a therapeutically effective amount of a method of treating a patient Suffering from a Sleep abnor Sedative agent and a therapeutically effective amount of a mality, comprising the Step of co-administering to a patient norepinephrine reuptake inhibitor; wherein Said Sedative in need thereof a therapeutically effective amount of a agent is racemic Zopiclone, eSZopiclone, indiplon, Zolpidem, US 2005/0176680 A1 Aug. 11, 2005 60

Zaleplon, gabOXadol, or a pharmaceutically acceptable Salt, mality, comprising the Step of co-administering to a patient Solvate, clathrate, polymorph, or co-crystal of any one of in need thereof a therapeutically effective amount of a them; and Said norepinephrine reuptake inhibitor is Sedative agent and a therapeutically effective amount of a desipramine, maprotiline, lofepramine, reboxetine, Oxapro 5-HT modulator; wherein said sedative agent is eSzopi tiline, feZolamine, tomoxetine, (S,S)-hydroxybupropion, or clone or a pharmaceutically acceptable Salt, Solvate, clath a pharmaceutically acceptable Salt, Solvate, clathrate, poly rate, polymorph, or co-crystal thereof, and said 5-HT2A morph, or co-crystal of any one of them. modulator is MDL 100907, SR 46349B, YM 992, fan 0659 Another aspect of the present invention relates to a anSerin, oxazolidine compounds A, phenylindole com method of treating a patient Suffering from a Sleep abnor pounds A, piperidinyl compounds B, Spiroazacyclic com mality, comprising the Step of co-administering to a patient pounds C, azacyclic compounds D, or a pharmaceutically in need thereof a therapeutically effective amount of a acceptable Salt, Solvate, clathrate, polymorph, or co-crystal Sedative agent and a therapeutically effective amount of a of any one of them. norepinephrine reuptake inhibitor; wherein Said Sedative 0664) Another aspect of the present invention relates to a agent is eSZopiclone or a pharmaceutically acceptable Salt, method of treating a patient Suffering from a Sleep abnor Solvate, clathrate, polymorph, or co-crystal thereof, and Said mality, comprising the Step of co-administering to a patient norepinephrine reuptake inhibitor is desipramine, mapro in need thereof a therapeutically effective amount of eSZopi tiline, lofepramine, reboxetine, Oxaprotiline, feZolamine, clone and a therapeutically effective amount of a 5-HT2A tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically modulator; wherein said 5-HT modulator is MDL 100907, acceptable Salt, Solvate, clathrate, polymorph, or co-crystal SR 46349B, YM 992, fananserin, or a pharmaceutically of any one of them. acceptable Salt, Solvate, clathrate, polymorph, or co-crystal 0660 Another aspect of the present invention relates to a of any one of them. method of treating a patient Suffering from a Sleep abnor 0665 Another aspect of the present invention relates to a mality, comprising the Step of co-administering to a patient method of treating a patient Suffering from a Sleep abnor in need thereof a therapeutically effective amount of eSZopi mality, comprising the Step of co-administering to a patient clone, or a pharmaceutically acceptable Salt, Solvate, clath in need thereof a therapeutically effective amount of a rate, polymorph, or co-crystal; and a therapeutically effec Sedative agent and a therapeutically effective amount of a tive amount of a norepinephrine reuptake inhibitor; wherein dopamine reuptake inhibitor; wherein Said Sedative agent is Said norepinephrine reuptake inhibitor is desipramine, a compound that modulates the activity of a GABA receptor reboxetine, Oxaprotiline, (S,S)-hydroxybupropion, or a phar and has a K, less than about 300 nM in a GABA-receptor maceutically acceptable Salt, Solvate, clathrate, polymorph, binding assay; and Said dopamine reuptake inhibitor is or co-crystal of any one of them. amineptine, bupropion, GBR-12935, Venlafaxine, 23-pro 0661 Another aspect of the present invention relates to a panoyl-3?-(4-tolyl)-tropane, or a pharmaceutically accept method of treating a patient Suffering from a Sleep abnor able Salt, Solvate, clathrate, polymorph, or co-crystal of any mality, comprising the Step of co-administering to a patient one of them. in need thereof a therapeutically effective amount of a 0.666 Another aspect of the present invention relates to a Sedative agent and a therapeutically effective amount of a method of treating a patient Suffering from a Sleep abnor 5-HT modulator; wherein said sedative agent is a com mality, comprising the Step of co-administering to a patient pound that modulates the activity of a GABA receptor and in need thereof a therapeutically effective amount of a has a Kless than about 300 nM in a GABA-receptor binding Sedative agent and a therapeutically effective amount of a assay; and said 5-HT modulator is MDL 100907, SR dopamine reuptake inhibitor; wherein Said Sedative agent is 46349B, YM 992, fananserin, oxazolidine compounds A, racemic Zopiclone, eSZopiclone, indiplon, Zolpidem, Zale phenylindole compounds A, piperidinyl compounds B, plon, gaboxadol, or a pharmaceutically acceptable Salt, Spiroazacyclic compounds C, azacyclic compounds D, or a Solvate, clathrate, polymorph, or co-crystal of any one of pharmaceutically acceptable Salt, Solvate, clathrate, poly them; and Said dopamine reuptake inhibitor is amineptine, morph, or co-crystal of any one of them. bupropion, GBR-12935, venlafaxine, 2B-propanoyl-3?-(4- 0662 Another aspect of the present invention relates to a tolyl)-tropane, or a pharmaceutically acceptable Salt, Sol method of treating a patient Suffering from a Sleep abnor Vate, clathrate, polymorph, or co-crystal of any one of them. mality, comprising the Step of co-administering to a patient 0667 Another aspect of the present invention relates to a in need thereof a therapeutically effective amount of a method of treating a patient Suffering from a Sleep abnor Sedative agent and a therapeutically effective amount of a mality, comprising the Step of co-administering to a patient 5-HT modulator; wherein said sedative agent is racemic in need thereof a therapeutically effective amount of a Zopiclone, eSZopiclone, indiplon, Zolpidem, Zaleplon, Sedative agent and a therapeutically effective amount of a gaboXadol, or a pharmaceutically acceptable Salt, Solvate, dopamine reuptake inhibitor; wherein Said Sedative agent is clathrate, polymorph, or co-crystal of any one of them; and eSZopiclone or a pharmaceutically acceptable Salt, Solvate, said 5-HT modulator is MDL 100907, SR 46349B, YM clathrate, polymorph, or co-crystal thereof, and Said dopam 992, fananserin, oxazolidine compounds A, phenylindole ine reuptake inhibitor is amineptine, bupropion, GBR compounds A, piperidinyl compounds B, Spiroazacyclic 12935, venlafaxine, 2B-propanoyl-3(3-(4-tolyl)-tropane, or a compounds C, azacyclic compounds D, or a pharmaceuti pharmaceutically acceptable Salt, Solvate, clathrate, poly cally acceptable Salt, Solvate, clathrate, polymorph, or co morph, or co-crystal of any one of them. crystal of any one of them. 0668. Another aspect of the present invention relates to a 0663 Another aspect of the present invention relates to a method of treating a patient Suffering from a Sleep abnor method of treating a patient Suffering from a Sleep abnor mality, comprising the Step of co-administering to a patient US 2005/0176680 A1 Aug. 11, 2005 in need thereof a therapeutically effective amount of eSZopi in need thereof a therapeutically effective amount of eSZopi clone or a pharmaceutically acceptable Salt, Solvate, clath clone or a pharmaceutically acceptable Salt, Solvate, clath rate, polymorph, or co-crystal thereof, and a therapeutically rate, polymorph, or co-crystal thereof; a therapeutically effective amount of bupropion or a pharmaceutically accept effective amount of fluoxetine hydrochloride or a pharma able Salt, Solvate, clathrate, polymorph, or co-crystal thereof. ceutically acceptable Salt, Solvate, clathrate, polymorph, or 0669. Another aspect of the present invention relates to a co-crystal thereof; and at least one pharmaceutically accept method of treating a patient Suffering from a Sleep abnor able carrier. mality, comprising the Step of co-administering to a patient 0674) Another aspect of the present invention relates to a in need thereof a therapeutically effective amount of a method of treating a patient Suffering from a Sleep abnor Sedative agent, a therapeutically effective amount of a Sero mality, comprising the Step of co-administering to a patient tonin reuptake inhibitor, and at least one pharmaceutically in need thereof a therapeutically effective amount of a acceptable carrier; wherein Said Sedative agent is a com Sedative agent, a therapeutically effective amount of a nore pound that modulates the activity of a GABA receptor and pinephrine reuptake inhibitor, and at least one pharmaceu has a Kless than about 300 nM in a GABA-receptor binding tically acceptable carrier; wherein Said Sedative agent is a assay; and Said Serotonin reuptake inhibitor is citalopram, compound that modulates the activity of a GABA receptor dulloxetine, escitalopram, fluoxetine, fluvoxamine, milnacip and has a K, less than about 300 nM in a GABA-receptor ran, paroxetine, Sertraline, clominpramine, femoxetine, binding assay; and Said norepinephrine reuptake inhibitor is indapline, alaprolclate, cericlamine, ifoxetine, or a pharma desipramine, maprotiline, lofepramine, reboxetine, Oxapro ceutically acceptable Salt, Solvate, clathrate, polymorph, or tiline, feZolamine, tomoxetine, (S,S)-hydroxybupropion, or co-crystal of any one of them. a pharmaceutically acceptable Salt, Solvate, clathrate, poly 0670 Another aspect of the present invention relates to a morph, or co-crystal of any one of them. method of treating a patient Suffering from a Sleep abnor 0675 Another aspect of the present invention relates to a mality, comprising the Step of co-administering to a patient method of treating a patient Suffering from a Sleep abnor in need thereof a therapeutically effective amount of a mality, comprising the Step of co-administering to a patient Sedative agent, a therapeutically effective amount of a Sero in need thereof a therapeutically effective amount of a tonin reuptake inhibitor, and at least one pharmaceutically Sedative agent, a therapeutically effective amount of a nore acceptable carrier; wherein Said Sedative agent is racemic pinephrine reuptake inhibitor, and at least one pharmaceu Zopiclone, eSZopiclone, indiplon, Zolpidem, Zaleplon, tically acceptable carrier, wherein Said Sedative agent is gaboXadol, or a pharmaceutically acceptable Salt, Solvate, racemic Zopiclone, eSZopiclone, indiplon, Zolpidem, Zale clathrate, polymorph, or co-crystal of any one of them; and plon, gaboxadol, or a pharmaceutically acceptable Salt, Said Serotonin reuptake inhibitor is citalopram, dulloxetine, Solvate, clathrate, polymorph, or co-crystal of any one of escitalopram, fluoxetine, fluvoxamine, milnacipran, paroX them; and Said norepinephrine reuptake inhibitor is etine, Sertraline, clominpramine, femoxetine, indapline, ala desipramine, maprotiline, lofepramine, reboxetine, Oxapro prolclate, cericlamine, ifoxetine, or a pharmaceutically tiline, feZolamine, tomoxetine, (S,S)-hydroxybupropion, or acceptable Salt, Solvate, clathrate, polymorph, or co-crystal a pharmaceutically acceptable Salt, Solvate, clathrate, poly of any one of them. morph, or co-crystal of any one of them. 0671 Another aspect of the present invention relates to a 0676 Another aspect of the present invention relates to a method of treating a patient Suffering from a Sleep abnor method of treating a patient Suffering from a Sleep abnor mality, comprising the Step of co-administering to a patient mality, comprising the Step of co-administering to a patient in need thereof a therapeutically effective amount of a in need thereof a therapeutically effective amount of a Sedative agent, a therapeutically effective amount of a Sero Sedative agent, a therapeutically effective amount of a nore tonin reuptake inhibitor, and at least one pharmaceutically pinephrine reuptake inhibitor, and at least one pharmaceu acceptable carrier; wherein Said Sedative agent is racemic tically acceptable carrier; wherein Said Sedative agent is Zopiclone, eSZopiclone, or a pharmaceutically acceptable eSZopiclone or a pharmaceutically acceptable Salt, Solvate, Salt, Solvate, clathrate, polymorph, or co-crystal of either of clathrate, polymorph, or co-crystal thereof, and Said nore them; and Said Serotonin reuptake inhibitor is fluoxetine, pinephrine reuptake inhibitor is desipramine, maprotiline, paroxetine, or a pharmaceutically acceptable Salt, Solvate, lofepramine, reboxetine, Oxaprotiline, feZolamine, tomoxet clathrate, polymorph, or co-crystal of either of them. ine, (S,S)-hydroxybupropion, or a pharmaceutically accept 0672 Another aspect of the present invention relates to a able Salt, Solvate, clathrate, polymorph, or co-crystal of any method of treating a patient Suffering from a Sleep abnor one of them. mality, comprising the Step of co-administering to a patient 0677 Another aspect of the present invention relates to a in need thereof a therapeutically effective amount of a method of treating a patient Suffering from a Sleep abnor Sedative agent, a therapeutically effective amount of a Sero mality, comprising the Step of co-administering to a patient tonin reuptake inhibitor, and at least one pharmaceutically in need thereof a therapeutically effective amount of eSZopi acceptable carrier; wherein Said Sedative agent is eSZopi clone or a pharmaceutically acceptable Salt, Solvate, clath clone or a pharmaceutically acceptable Salt, Solvate, clath rate, polymorph, or co-crystal thereof, a therapeutically rate, polymorph, or co-crystal thereof; and Said Serotonin effective amount of a norepinephrine reuptake inhibitor, and reuptake inhibitor is fluoxetine or a pharmaceutically accept at least one pharmaceutically acceptable carrier; wherein able Salt, Solvate, clathrate, polymorph, or co-crystal thereof Said norepinephrine reuptake inhibitor is desipramine, 0673. Another aspect of the present invention relates to a reboxetine, Oxaprotiline, (S,S)-hydroxybupropion, or a phar method of treating a patient Suffering from a Sleep abnor maceutically acceptable Salt, Solvate, clathrate, polymorph, mality, comprising the Step of co-administering to a patient or co-crystal of any one of them. US 2005/0176680 A1 Aug. 11, 2005 62

0678. Another aspect of the present invention relates to a cally acceptable carrier; wherein Said Sedative agent is a method of treating a patient Suffering from a Sleep abnor compound that modulates the activity of a GABA receptor mality, comprising the Step of co-administering to a patient and has a K, less than about 300 nM in a GABA-receptor in need thereof a therapeutically effective amount of a binding assay; and Said dopamine reuptake inhibitor is Sedative agent, a therapeutically effective amount of a amineptine, bupropion, GBR-12935, Venlafaxine, 23-pro 5-HT modulator, and at least one pharmaceutically accept panoyl-3?-(4-tolyl)-tropane, or a pharmaceutically accept able carrier; wherein Said Sedative agent is a compound that able Salt, Solvate, clathrate, polymorph, or co-crystal of any modulates the activity of a GABA receptor and has a KleSS one of them. than about 300 nM in a GABA-receptor binding assay; and said 5-HT modulator is MDL 100907, SR 46349B, YM 0683 Another aspect of the present invention relates to a 992, fananserin, oxazolidine compounds A, phenylindole method of treating a patient Suffering from a Sleep abnor compounds A, piperidinyl compounds B, Spiroazacyclic mality, comprising the Step of co-administering to a patient compounds C, azacyclic compounds D, or a pharmaceuti in need thereof a therapeutically effective amount of a Sedative agent, a therapeutically effective amount of a cally acceptable Salt, Solvate, clathrate, polymorph, or co dopamine reuptake inhibitor, and at least one pharmaceuti crystal of any one of them. cally acceptable carrier; wherein Said Sedative agent is 0679. Another aspect of the present invention relates to a racemic Zopiclone, eSZopiclone, indiplon, Zolpidem, Zale method of treating a patient Suffering from a Sleep abnor plon, gaboxadol, or a pharmaceutically acceptable Salt, mality, comprising the Step of co-administering to a patient Solvate, clathrate, polymorph, or co-crystal of any one of in need thereof a therapeutically effective amount of a them; and Said dopamine reuptake inhibitor is amineptine, Sedative agent, a therapeutically effective amount of a bupropion, GBR-12935, venlafaxine, 2B-propanoyl-3?-(4- 5-HT modulator, and at least one pharmaceutically accept tolyl)-tropane, or a pharmaceutically acceptable Salt, Sol able carrier; wherein Said Sedative agent is racemic Zopi Vate, clathrate, polymorph, or co-crystal of any one of them. clone, eSZopiclone, indiplon, Zolpidem, Zaleplon, gaboxadol, or a pharmaceutically acceptable Salt, Solvate, clathrate, 0684 Another aspect of the present invention relates to a polymorph, or co-crystal of any one of them; and Said method of treating a patient Suffering from a Sleep abnor 5-HT modulator is MDL 100907, SR 46349B, YM 992, mality, comprising the Step of co-administering to a patient fananserin, oxazolidine compounds A, phenylindole com in need thereof a therapeutically effective amount of a pounds A, piperidinyl compounds B, Spiroazacyclic com Sedative agent, a therapeutically effective amount of a pounds C, azacyclic compounds D, or a pharmaceutically dopamine reuptake inhibitor, and at least one pharmaceuti cally acceptable carrier; wherein Said Sedative agent is acceptable Salt, Solvate, clathrate, polymorph, or co-crystal eSZopiclone or a pharmaceutically acceptable Salt, Solvate, of any one of them. clathrate, polymorph, or co-crystal thereof, and Said dopam 0680 Another aspect of the present invention relates to a ine reuptake inhibitor is amineptine, bupropion, GBR method of treating a patient Suffering from a Sleep abnor 12935, venlafaxine, 2B-propanoyl-3(3-(4-tolyl)-tropane, or a mality, comprising the Step of co-administering to a patient pharmaceutically acceptable Salt, Solvate, clathrate, poly in need thereof a therapeutically effective amount of a morph, or co-crystal of any one of them. Sedative agent, a therapeutically effective amount of a 5-HT modulator, and at least one pharmaceutically accept 0685 Another aspect of the present invention relates to a able carrier; wherein Said Sedative agent is eSZopiclone or a method of treating a patient Suffering from a Sleep abnor pharmaceutically acceptable Salt, Solvate, clathrate, poly mality, comprising the Step of co-administering to a patient morph, or co-crystal thereof; and Said 5-HT2A modulator is in need thereof a therapeutically effective amount of eSZopi MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine clone or a pharmaceutically acceptable Salt, Solvate, clath compounds A, phenylindole compounds A, piperidinyl com rate, polymorph, or co-crystal thereof, and a therapeutically pounds B, Spiroazacyclic compounds C, azacyclic com effective amount of bupropion or a pharmaceutically accept pounds D, or a pharmaceutically acceptable Salt, Solvate, able Salt, Solvate, clathrate, polymorph, or co-crystal thereof, clathrate, polymorph, or co-crystal of any one of them. and at least one pharmaceutically acceptable carrier. 0686. In certain embodiments, the present invention 0681 Another aspect of the present invention relates to a relates to the aforementioned methods, wherein Said Sleep method of treating a patient Suffering from a Sleep abnor disturbance is difficulty falling asleep, difficulty Staying mality, comprising the Step of co-administering to a patient asleep, or waking up too early. in need thereof a therapeutically effective amount of eSZopi clone, or a pharmaceutically acceptable Salt, Solvate, clath 0687 Another aspect of the present invention relates rate, polymorph, or co-crystal of any one of them; a thera generally to a method of treating a patient Suffering from peutically effective amount of a 5-HTA modulator; and at insomnia, comprising the Step of co-administering to a least one pharmaceutically acceptable carrier; wherein Said patient in need thereof a therapeutically effective amount of 5-HT, modulator is MDL 100907, SR 46349B, YM 992, a Sedative and a therapeutically effective amount of an fananserin, or a pharmaceutically acceptable Salt, Solvate, antidepressant, wherein Said Sedative agent is a compound clathrate, polymorph, or co-crystal of any one of them. that modulates the activity of a GABA receptor and has a K. less than about 300 nM in a GABA-receptor binding assay; 0682 Another aspect of the present invention relates to a and Said antidepressant is a Serotonin reuptake inhibitor, method of treating a patient Suffering from a Sleep abnor norepinephrine reuptake inhibitor, 5HT2A modulator, or mality, comprising the Step of co-administering to a patient dopamine reuptake inhibitor. in need thereof a therapeutically effective amount of a Sedative agent, a therapeutically effective amount of a 0688. In certain embodiments, the present invention dopamine reuptake inhibitor, and at least one pharmaceuti relates to the aforementioned method, wherein Said Sedative US 2005/0176680 A1 Aug. 11, 2005 is racemic Zopiclone, (S)-Zopiclone, indiplon, Zolpidem, rate, polymorph, or co-crystal thereof; and Said Serotonin Zaleplon, gabOXadol, or a pharmaceutically acceptable Salt, reuptake inhibitor is fluoxetine or a pharmaceutically accept Solvate, or hydrate of any one of them; and Said antidepres able Salt, Solvate, clathrate, polymorph, or co-crystal thereof. Sant is citalopram, dulloxetine, escitalopram, fluoxetine, flu 0.693. Another aspect of the present invention relates to a Voxamine, milnacipran, paroxetine, Sertraline, clomin method of treating a patient Suffering from insomnia, com pramine, femoxetine, indapline, alaprolclate, cericlamine, prising the Step of co-administering to a patient in need ifoxetine, desipramine, maprotiline, lofepramine, reboxet thereof a therapeutically effective amount of eSZopiclone or ine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybu a pharmaceutically acceptable Salt, Solvate, clathrate, poly propion, MDL 100907, SR 46349B, YM 992, fananserin, morph, or co-crystal thereof; and a therapeutically effective Oxazolidine compounds A, phenylindole compounds A, pip amount of fluoxetine hydrochloride or a pharmaceutically eridinyl compounds B, Spiroazacyclic compounds C, aza acceptable Salt, Solvate, clathrate, polymorph, or co-crystal cyclic compounds D, amineptine, bupropion, GBR-12935, Venlafaxine, or 2,3-propanoyl-3B-(4-tolyl)-tropane, or a thereof. pharmaceutically acceptable Salt, Solvate, or hydrate of any 0694. Another aspect of the present invention relates to a one of them. method of treating a patient Suffering from insomnia, com prising the Step of co-administering to a patient in need 0689 Another aspect of the present invention relates to a thereof a therapeutically effective amount of a Sedative agent method of treating a patient Suffering from insomnia, com and a therapeutically effective amount of a norepinephrine prising the Step of co-administering to a patient in need reuptake inhibitor; wherein Said Sedative agent is a com thereofatherapeutically effective amount of a Sedative agent pound that modulates the activity of a GABA receptor and and a therapeutically effective amount of a Serotonin has a Kless than about 300 nM in a GABA-receptor binding reuptake inhibitor; wherein Said Sedative agent is a com assay; and Said norepinephrine reuptake inhibitor is pound that modulates the activity of a GABA receptor and desipramine, maprotiline, lofepramine, reboxetine, Oxapro has a Kless than about 300 nM in a GABA-receptor binding tiline, feZolamine, tomoxetine, (S,S)-hydroxybupropion, or assay; and Said Serotonin reuptake inhibitor is citalopram, a pharmaceutically acceptable Salt, Solvate, clathrate, poly dulloxetine, escitalopram, fluoxetine, fluvoxamine, milnacip morph, or co-crystal of any one of them. ran, paroxetine, Sertraline, clominpramine, femoxetine, 0695) Another aspect of the present invention relates to a indapline, alaprolclate, cericlamine, ifoxetine, or a pharma method of treating a patient Suffering from insomnia, com ceutically acceptable Salt, Solvate, clathrate, polymorph, or prising the Step of co-administering to a patient in need co-crystal of any one of them. thereof a therapeutically effective amount of a Sedative agent 0690 Another aspect of the present invention relates to a and a therapeutically effective amount of a norepinephrine method of treating a patient Suffering from insomnia, com reuptake inhibitor, wherein Said Sedative agent is racemic prising the Step of co-administering to a patient in need Zopiclone, eSZopiclone, indiplon, Zolpidem, Zaleplon, thereofatherapeutically effective amount of a Sedative agent gaboXadol, or a pharmaceutically acceptable Salt, Solvate, and a therapeutically effective amount of a Serotonin clathrate, polymorph, or co-crystal of any one of them; and reuptake inhibitor, wherein Said Sedative agent is racemic Said norepinephrine reuptake inhibitor is desipramine, Zopiclone, eSZopiclone, indiplon, Zolpidem, Zaleplon, maprotiline, lofepramine, reboxetine, Oxaprotiline, feZola gaboXadol, or a pharmaceutically acceptable Salt, Solvate, mine, tomoxetine, (S,S)-hydroxybupropion, or a pharma clathrate, polymorph, or co-crystal of any one of them; and ceutically acceptable Salt, Solvate, clathrate, polymorph, or Said Serotonin reuptake inhibitor is citalopram, dulloxetine, co-crystal of any one of them. escitalopram, fluoxetine, fluvoxamine, milnacipran, paroX 0696. Another aspect of the present invention relates to a etine, Sertraline, clominpramine, femoxetine, indapline, ala method of treating a patient Suffering from insomnia, com prolclate, cericlamine, ifoxetine, or a pharmaceutically prising the Step of co-administering to a patient in need acceptable Salt, Solvate, clathrate, polymorph, or co-crystal thereof a therapeutically effective amount of a Sedative agent of any one of them. and a therapeutically effective amount of a norepinephrine reuptake inhibitor; wherein Said Sedative agent is eSZopi 0691 Another aspect of the present invention relates to a clone or a pharmaceutically acceptable Salt, Solvate, clath method of treating a patient Suffering from insomnia, com rate, polymorph, or co-crystal thereof, and Said norepineph prising the Step of co-administering to a patient in need rine reuptake inhibitor is desipramine, maprotiline, thereofatherapeutically effective amount of a Sedative agent lofepramine, reboxetine, Oxaprotiline, feZolamine, tomoxet and a therapeutically effective amount of a Serotonin ine, (S,S)-hydroxybupropion, or a pharmaceutically accept reuptake inhibitor, wherein Said Sedative agent is racemic able Salt, Solvate, clathrate, polymorph, or co-crystal of any Zopiclone, eSZopiclone, or a pharmaceutically acceptable one of them. Salt, Solvate, clathrate, polymorph, or co-crystal of either of them; and Said Serotonin reuptake inhibitor is fluoxetine, 0697 Another aspect of the present invention relates to a paroxetine, or a pharmaceutically acceptable Salt, Solvate, method of treating a patient Suffering from insomnia, com clathrate, polymorph, or co-crystal of either of them. prising the Step of co-administering to a patient in need thereof a therapeutically effective amount of eSZopiclone, or 0692 Another aspect of the present invention relates to a a pharmaceutically acceptable Salt, Solvate, clathrate, poly method of treating a patient Suffering from insomnia, com morph, or co-crystal; and a therapeutically effective amount prising the Step of co-administering to a patient in need of a norepinephrine reuptake inhibitor; wherein Said nore thereofatherapeutically effective amount of a Sedative agent pinephrine reuptake inhibitor is desipramine, reboxetine, and a therapeutically effective amount of a Serotonin Oxaprotiline, (S,S)-hydroxybupropion, or a-pharmaceuti reuptake inhibitor; wherein Said Sedative agent is eSZopi cally acceptable Salt, Solvate, clathrate, polymorph, or co clone or a pharmaceutically acceptable Salt, Solvate, clath crystal of any one of them. US 2005/0176680 A1 Aug. 11, 2005 64

0698 Another aspect of the present invention relates to a 0703. Another aspect of the present invention relates to a method of treating a patient Suffering from insomnia, com method of treating a patient Suffering from insomnia, com prising the Step of co-administering to a patient in need prising the Step of co-administering to a patient in need thereofatherapeutically effective amount of a Sedative agent thereof a therapeutically effective amount of a Sedative agent and a therapeutically effective amount of a 5-HTA modu and a therapeutically effective amount of a dopamine lator; wherein Said Sedative agent is a compound that reuptake inhibitor, wherein Said Sedative agent is racemic modulates the activity of a GABA receptor and has a KleSS Zopiclone, eSZopiclone, indiplon, Zolpidem, Zaleplon, than about 300 nM in a GABA-receptor binding assay; and gaboXadol, or a pharmaceutically acceptable Salt, Solvate, said 5-HT modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole clathrate, polymorph, or co-crystal of any one of them; and compounds A, piperidinyl compounds B, Spiroazacyclic Said dopamine reuptake inhibitor is amineptine, bupropion, compounds C, azacyclic compounds D, or a pharmaceuti GBR-12935, venlafaxine, 2B-propanoyl-3?-(4-tolyl)-tro cally acceptable Salt, Solvate, clathrate, polymorph, or co pane, or a pharmaceutically acceptable Salt, Solvate, clath crystal of any one of them. rate, polymorph, or co-crystal of any one of them. 0699 Another aspect of the present invention relates to a 0704. Another aspect of the present invention relates to a method of treating a patient Suffering from insomnia, com method of treating a patient Suffering from insomnia, com prising the Step of co-administering to a patient in need prising the Step of co-administering to a patient in need thereofatherapeutically effective amount of a Sedative agent thereof a therapeutically effective amount of a Sedative agent and a therapeutically effective amount of a 5-HTA modu and a therapeutically effective amount of a dopamine lator; wherein Said Sedative agent is racemic Zopiclone, reuptake inhibitor; wherein Said Sedative agent is eSZopi eSZopiclone, indiplon, Zolpidem, Zaleplon, gabOXadol, or a clone or a pharmaceutically acceptable Salt, Solvate, clath pharmaceutically acceptable Salt, Solvate, clathrate, poly rate, polymorph, or co-crystal thereof, and Said dopamine morph, or co-crystal of any one of them; and Said 5-HT2A reuptake inhibitor is amineptine, bupropion, GBR-12935, modulator is MDL 100907, SR 46349B, YM 992, fan Venlafaxine, 2(3-propanoyl-3?-(4-tolyl)-tropane, or a phar anSerin, oxazolidine compounds A, phenylindole com maceutically acceptable Salt, Solvate, clathrate, polymorph, pounds A, piperidinyl compounds B, Spiroazacyclic com or co-crystal of any one of them. pounds C, azacyclic compounds D, or a pharmaceutically acceptable Salt, Solvate, clathrate, polymorph, or co-crystal 0705) Another aspect of the present invention relates to a of any one of them. method of treating a patient Suffering from insomnia, com prising the Step of co-administering to a patient in need 0700 Another aspect of the present invention relates to a thereof a therapeutically effective amount of eSZopiclone or method of treating a patient Suffering from insomnia, com a pharmaceutically acceptable Salt, Solvate, clathrate, poly prising the Step of co-administering to a patient in need morph, or co-crystal thereof; and a therapeutically effective thereofatherapeutically effective amount of a Sedative agent amount of bupropion or a pharmaceutically acceptable Salt, and a therapeutically effective amount of a 5-HTA modu lator; wherein Said Sedative agent is eSZopiclone or a phar Solvate, clathrate, polymorph, or co-crystal thereof. maceutically acceptable Salt, Solvate, clathrate, polymorph, 0706. Another aspect of the present invention relates to a or co-crystal thereof; and said 5-HTA modulator is MDL method of treating a patient Suffering from insomnia, com 100907, SR 46349B, YM 992, fananserin, oxazolidine com prising the Step of co-administering to a patient in need pounds A, phenylindole compounds A, piperidinyl com thereof a therapeutically effective amount of a Sedative pounds B, Spiroazacyclic compounds C, azacyclic com agent, a therapeutically effective amount of a Serotonin pounds D, or a pharmaceutically acceptable Salt, Solvate, reuptake inhibitor, and at least one pharmaceutically accept clathrate, polymorph, or co-crystal of any one of them. able carrier; wherein Said Sedative agent is a compound that 0701] Another aspect of the present invention relates to a modulates the activity of a GABA receptor and has a KleSS method of treating a patient Suffering from insomnia, com than about 300 nM in a GABA-receptor binding assay; and prising the Step of co-administering to a patient in need Said Serotonin reuptake inhibitor is citalopram, dulloxetine, thereof a therapeutically effective amount of eSZopiclone escitalopram, fluoxetine, fluvoxamine, milnacipran, paroX and a therapeutically effective amount of a 5-HTA modu etine, Sertraline, clominpramine, femoxetine, indapline, ala lator; wherein said 5-HT, modulator is MDL 100907, SR prolclate, cericlamine, ifoxetine, or a pharmaceutically 46349B, YM 992, fananserin, or a pharmaceutically accept acceptable Salt, Solvate, clathrate, polymorph, or co-crystal able Salt, Solvate, clathrate, polymorph, or co-crystal of any of any one of them. one of them. 0707 Another aspect of the present invention relates to a 0702 Another aspect of the present invention relates to a method of treating a patient Suffering from insomnia, com method of treating a patient Suffering from insomnia, com prising the Step of co-administering to a patient in need prising the Step of co-administering to a patient in need thereof a therapeutically effective amount of a Sedative thereofatherapeutically effective amount of a Sedative agent agent, a therapeutically effective amount of a Serotonin and a therapeutically effective amount of a dopamine reuptake inhibitor, and at least one pharmaceutically accept reuptake inhibitor; wherein Said Sedative agent is a com able carrier; wherein Said Sedative agent is racemic Zopi pound that modulates the activity of a GABA receptor and clone, eSZopiclone, indiplon, Zolpidem, Zaleplon, gaboxadol, has a Kless than about 300 nM in a GABA-receptor binding or a pharmaceutically acceptable Salt, Solvate, clathrate, assay; and Said dopamine reuptake inhibitor is amineptine, polymorph, or co-crystal of any one of them; and Said bupropion, GBR-12935, venlafaxine, 2B-propanoyl-3?-(4- Serotonin reuptake inhibitor is citalopram, dulloxetine, esci tolyl)-tropane, or a pharmaceutically acceptable Salt, Sol talopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, Vate, clathrate, polymorph, or co-crystal of any one of them. Sertraline, clominpramine, femoxetine, indapline, alapro US 2005/0176680 A1 Aug. 11, 2005 lclate, cericlamine, ifoxetine, or a pharmaceutically accept tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically able Salt, Solvate, clathrate, polymorph, or co-crystal of any acceptable Salt, Solvate, clathrate, polymorph, or co-crystal one of them. of any one of them. 0708 Another aspect of the present invention relates to a 0713 Another aspect of the present invention relates to a method of treating a patient Suffering from insomnia, com method of treating a patient Suffering from insomnia, com prising the Step of co-administering to a patient in need prising the Step of co-administering to a patient in need thereof a therapeutically effective amount of a Sedative thereof a therapeutically effective amount of a Sedative agent, a therapeutically effective amount of a Serotonin agent, a therapeutically effective amount of a norepinephrine reuptake inhibitor, and at least one pharmaceutically accept reuptake inhibitor, and at least one pharmaceutically accept able carrier; wherein Said Sedative agent is racemic Zopi able carrier; wherein Said Sedative agent is eSZopiclone or a clone, eSZopiclone, or a pharmaceutically acceptable Salt, pharmaceutically acceptable Salt, Solvate, clathrate, poly Solvate, clathrate, polymorph, or co-crystal of either of them; morph, or co-crystal thereof, and Said norepinephrine and Said Serotonin reuptake inhibitor is fluoxetine, paroxet reuptake inhibitor is desipramine, maprotiline, lofepramine, ine, or a pharmaceutically acceptable Salt, Solvate, clathrate, reboxetine, Oxaprotiline, fezolamine, tomoxetine, (S,S)-hy polymorph, or co-crystal of either of them. droxybupropion, or a pharmaceutically acceptable Salt, Sol Vate, clathrate, polymorph, or co-crystal of any one of them. 0709 Another aspect of the present invention relates to a 0714 Another aspect of the present invention relates to a method of treating a patient Suffering from insomnia, com method of treating a patient Suffering from insomnia, com prising the Step of co-administering to a patient in need prising the Step of co-administering to a patient in need thereof a therapeutically effective amount of a Sedative thereof a therapeutically effective amount of eSZopiclone or agent, a therapeutically effective amount of a Serotonin a pharmaceutically acceptable Salt, Solvate, clathrate, poly reuptake inhibitor, and at least one pharmaceutically accept morph, or co-crystal thereof; a therapeutically effective able carrier; wherein Said Sedative agent is eSZopiclone or a amount of a norepinephrine reuptake inhibitor; and at least pharmaceutically acceptable Salt, Solvate, clathrate, poly one pharmaceutically acceptable carrier; wherein Said nore morph, or co-crystal thereof; and Said Serotonin reuptake pinephrine reuptake inhibitor is desipramine, reboxetine, inhibitor is fluoxetine or a pharmaceutically acceptable Salt, Oxaprotiline, (S,S)-hydroxybupropion, or a pharmaceuti Solvate, clathrate, polymorph, or co-crystal thereof. cally acceptable Salt, Solvate, clathrate, polymorph, or co 0710 Another aspect of the present invention relates to a crystal of any one of them. method of treating a patient Suffering from insomnia, com 0715) Another aspect of the present invention relates to a prising the Step of co-administering to a patient in need method of treating a patient Suffering from insomnia, com thereof a therapeutically effective amount of eSZopiclone or prising the Step of co-administering to a patient in need a pharmaceutically acceptable Salt, Solvate, clathrate, poly thereof a therapeutically effective amount of a Sedative morph, or co-crystal thereof; a therapeutically effective agent, a therapeutically effective amount of a 5-HTA modu amount of fluoxetine hydrochloride or a pharmaceutically lator, and at least one pharmaceutically acceptable carrier; acceptable Salt, Solvate, clathrate, polymorph, or co-crystal wherein Said Sedative agent is a compound that modulates thereof, and at least one pharmaceutically acceptable carrier. the activity of a GABA receptor and has a KleSS than about 0711) Another aspect of the present invention relates to a 300 nM in a GABA-receptor binding assay; and said 5-HT2A method of treating a patient Suffering from insomnia, com modulator is MDL 100907, SR 46349B, YM 992, fan prising the Step of co-administering to a patient in need anSerin, oxazolidine compounds A, phenylindole com thereof a therapeutically effective amount of a Sedative pounds A, piperidinyl compounds B, Spiroazacyclic com agent, a therapeutically effective amount of a norepinephrine pounds C, azacyclic compounds D, or a pharmaceutically reuptake inhibitor, and at least one pharmaceutically accept acceptable Salt, Solvate, clathrate, polymorph, or co-crystal able carrier; wherein Said Sedative agent is a compound that of any one of them. modulates the activity of a GABA receptor and has a Kless 0716. Another aspect of the present invention relates to a than about 300 nM in a GABA-receptor binding assay; and method of treating a patient Suffering from insomnia, com Said norepinephrine reuptake inhibitor is desipramine, prising the Step of co-administering to a patient in need maprotiline, lofepramine, reboxetine, Oxaprotiline, feZola thereof a therapeutically effective amount of a Sedative mine, tomoxetine, (S,S)-hydroxybupropion, or a pharma agent, a therapeutically effective amount of a 5-HTA modu ceutically acceptable Salt, Solvate, clathrate, polymorph, or lator, and at least one pharmaceutically acceptable carrier; co-crystal of any one of them. wherein Said Sedative agent is racemic Zopiclone, eSZopi clone, indiplon, Zolpidem, Zaleplon, gaboxadol, or a phar 0712. Another aspect of the present invention relates to a maceutically acceptable Salt, Solvate, clathrate, polymorph, method of treating a patient Suffering from insomnia, com or co-crystal of any one of them; and Said 5-HTA modulator prising the Step of co-administering to a patient in need is MDL 100907, SR 46349B, YM 992, fananserin, oxazo thereof a therapeutically effective amount of a Sedative lidine compounds A, phenylindole compounds A, piperidi agent, a therapeutically effective amount of a norepinephrine nyl compounds B, Spiroazacyclic compounds C, azacyclic reuptake inhibitor, and at least one pharmaceutically accept compounds D, or a pharmaceutically acceptable Salt, Sol able carrier; wherein Said Sedative agent is racemic Zopi clone, eSZopiclone, indiplon, Zolpidem, Zaleplon, gaboxadol, Vate, clathrate, polymorph, or co-crystal of any one of them. or a pharmaceutically acceptable Salt, Solvate, clathrate, 0717. Another aspect of the present invention relates to a polymorph, or co-crystal of any one of them; and Said method of treating a patient Suffering from insomnia, com norepinephrine reuptake inhibitor is desipramine, mapro prising the Step of co-administering to a patient in need tiline, lofepramine, reboxetine, Oxaprotiline, feZolamine, thereof a therapeutically effective amount of a Sedative US 2005/0176680 A1 Aug. 11, 2005 66 agent, a therapeutically effective amount of a 5-HTA modu prising the Step of co-administering to a patient in need lator, and at least one pharmaceutically acceptable carrier; thereof a therapeutically effective amount of eSZopiclone or wherein Said Sedative agent is eSZopiclone or a pharmaceu a pharmaceutically acceptable Salt, Solvate, clathrate, poly tically acceptable Salt, Solvate, clathrate, polymorph, or morph, or co-crystal thereof; and a therapeutically effective co-crystal thereof; and said 5-HT modulator is MDL amount of bupropion or a pharmaceutically acceptable Salt, 100907, SR 46349B, YM 992, fananserin, oxazolidine com Solvate, clathrate, polymorph, or co-crystal thereof, and at pounds A, phenylindole compounds A, piperidinyl com least one pharmaceutically acceptable carrier. pounds B, Spiroazacyclic compounds C, azacyclic com 0723. In certain embodiments, the present invention pounds D, or a pharmaceutically acceptable Salt, Solvate, relates to the aforementioned methods, wherein Said insom clathrate, polymorph, or co-crystal of any one of them. nia is transient insomnia. 0718. Another aspect of the present invention relates to a method of treating a patient Suffering from insomnia, com 0724. In certain embodiments, the present invention prising the Step of co-administering to a patient in need relates to the aforementioned methods, wherein Said insom thereof a therapeutically effective amount of eSZopiclone, or nia is short-term insomnia. a pharmaceutically acceptable Salt, Solvate, clathrate, poly 0725. In certain embodiments, the present invention morph, or co-crystal of any one of them; a therapeutically relates to the aforementioned methods, wherein Said insom effective amount of a 5-HT modulator; and at least one nia is chronic insomnia. pharmaceutically acceptable carrier; wherein Said 5-HTA modulator is MDL 100907, SR 46349B, YM 992, fan 0726. Another aspect of the present invention relates anSerin, or a pharmaceutically acceptable Salt, Solvate, clath generally to a method of treating a patient Suffering from rate, polymorph, or co-crystal of any one of them. depression, comprising the Step of co-administering to a patient in need thereof a therapeutically effective amount of 0719. Another aspect of the present invention relates to a a Sedative and a therapeutically effective amount of an method of treating a patient Suffering from insomnia, com antidepressant, wherein Said Sedative agent is a compound prising the Step of co-administering to a patient in need that modulates the activity of a GABA receptor and has a K. thereof a therapeutically effective amount of a Sedative less than about 300 nM in a GABA-receptor binding assay; agent, a therapeutically effective amount of a dopamine and Said antidepressant is a Serotonin reuptake inhibitor, reuptake inhibitor, and at least one pharmaceutically accept norepinephrine reuptake inhibitor, 5HT2A modulator, or able carrier; wherein Said Sedative agent is a compound that dopamine reuptake inhibitor. modulates the activity of a GABA receptor and has a Kless than about 300 nM in a GABA-receptor binding assay; and 0727. In certain embodiments, the present invention Said dopamine reuptake inhibitor is amineptine, bupropion, relates to the aforementioned method, wherein Said Sedative GBR-12935, venlafaxine, 2B-propanoyl-3?-(4-tolyl)-tro is racemic Zopiclone, (S)-Zopiclone, indiplon, Zolpidem, pane, or a pharmaceutically acceptable Salt, Solvate, clath Zaleplon, gaboxadol, or a pharmaceutically acceptable Salt, rate, polymorph, or co-crystal of any one of them. Solvate, or hydrate of any one of them; and Said antidepres 0720 Another aspect of the present invention relates to a Sant is citalopram, dulloxetine, escitalopram, fluoxetine, flu method of treating a patient Suffering from insomnia, com VOXamine, milnacipran, paroxetine, Sertraline, clomin prising the Step of co-administering to a patient in need pramine, femoxetine, indapline, alaprolclate, cericlamine, thereof a therapeutically effective amount of a Sedative ifoxetine, desipramine, maprotiline, lofepramine, reboxet agent, a therapeutically effective amount of a dopamine ine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybu reuptake inhibitor, and at least one pharmaceutically accept propion, MDL 100907, SR 46349B, YM 992, fananserin, able carrier; wherein Said Sedative agent is racemic Zopi Oxazolidine compounds A, phenylindole compounds A, pip clone, eSZopiclone, indiplon, Zolpidem, Zaleplon, gaboxadol, eridinyl compounds B, Spiroazacyclic compounds C, aza or a pharmaceutically acceptable Salt, Solvate, clathrate, cyclic compounds D, amineptine, bupropion, GBR-12935, polymorph, or co-crystal of any one of them; and Said Venlafaxine, or 2,3-propanoyl-3B-(4-tolyl)-tropane, or a dopamine reuptake inhibitor is amineptine, bupropion, pharmaceutically acceptable Salt, Solvate, or hydrate of any GBR-12935, venlafaxine, 2B-propanoyl-3?-(4-tolyl)-tro one of them. pane, or a pharmaceutically acceptable Salt, Solvate, clath 0728. Another aspect of the present invention relates to a rate, polymorph, or co-crystal of any one of them. method of treating a patient Suffering from depression, 0721 Another aspect of the present invention relates to a comprising the Step of co-administering to a patient in need method of treating a patient Suffering from insomnia, com thereof a therapeutically effective amount of a Sedative agent prising the Step of co-administering to a patient in need and a therapeutically effective amount of a Serotonin thereof a therapeutically effective amount of a Sedative reuptake inhibitor; wherein Said Sedative agent is a com agent, a therapeutically effective amount of a dopamine pound that modulates the activity of a GABA receptor and reuptake inhibitor, and at least one pharmaceutically accept has a Kless than about 300 nM in a GABA-receptor binding able carrier; wherein Said Sedative agent is eSZopiclone or a assay; and Said Serotonin reuptake inhibitor is citalopram, pharmaceutically acceptable Salt, Solvate, clathrate, poly dulloxetine, escitalopram, fluoxetine, fluvoxamine, milnacip morph, or co-crystal thereof, and Said dopamine reuptake ran, paroxetine, Sertraline, clominpramine, femoxetine, inhibitor is amineptine, bupropion, GBR-12935, venlafax indapline, alaprolclate, cericlamine, ifoxetine, or a pharma ine, 2(3-propanoyl-3?-(4-tolyl)-tropane, or a pharmaceuti ceutically acceptable Salt, Solvate, clathrate, polymorph, or cally acceptable Salt, Solvate, clathrate, polymorph, or co co-crystal of any one of them. crystal of any one of them. 0729) Another aspect of the present invention relates to a 0722) Another aspect of the present invention relates to a method of treating a patient Suffering from depression, method of treating a patient Suffering from insomnia, com comprising the Step of co-administering to a patient in need US 2005/0176680 A1 Aug. 11, 2005 67 thereofatherapeutically effective amount of a Sedative agent gaboXadol, or a pharmaceutically acceptable Salt, Solvate, and a therapeutically effective amount of a Serotonin clathrate, polymorph, or co-crystal of any one of them; and reuptake inhibitor, wherein Said Sedative agent is racemic Said norepinephrine reuptake inhibitor is desipramine, Zopiclone, eSZopiclone, indiplon, Zolpidem, Zaleplon, maprotiline, lofepramine, reboxetine, Oxaprotiline, feZola gaboXadol, or a pharmaceutically acceptable Salt, Solvate, mine, tomoxetine, (S,S)-hydroxybupropion, or a pharma clathrate, polymorph, or co-crystal of any one of them; and ceutically acceptable Salt, Solvate, clathrate, polymorph, or Said Serotonin reuptake inhibitor is citalopram, dulloxetine, co-crystal of any one of them. escitalopram, fluoxetine, fluvoxamine, milnacipran, paroX 0735. Another aspect of the present invention relates to a etine, Sertraline, clominpramine, femoxetine, indapline, ala method of treating a patient Suffering from depression, prolclate, cericlamine, ifoxetine, or a pharmaceutically comprising the Step of co-administering to a patient in need acceptable Salt, Solvate, clathrate, polymorph, or co-crystal thereof a therapeutically effective amount of a Sedative agent of any one of them. and a therapeutically effective amount of a norepinephrine 0730. Another aspect of the present invention relates to a reuptake inhibitor; wherein Said Sedative agent is eSZopi method of treating a patient Suffering from depression, clone or a pharmaceutically acceptable Salt, Solvate, clath comprising the Step of co-administering to a patient in need rate, polymorph, or co-crystal thereof, and Said norepineph thereofatherapeutically effective amount of a Sedative agent rine reuptake inhibitor is desipramine, maprotiline, and a therapeutically effective amount of a Serotonin lofepramine, reboxetine, Oxaprotiline, feZolamine, tomoxet reuptake inhibitor, wherein Said Sedative agent is racemic ine, (S,S)-hydroxybupropion, or a pharmaceutically accept Zopiclone, eSZopiclone, or a pharmaceutically acceptable able Salt, Solvate, clathrate, polymorph, or co-crystal of any Salt, Solvate, clathrate, polymorph, or co-crystal of either of one of them. them; and Said Serotonin reuptake inhibitor is fluoxetine, 0736. Another aspect of the present invention relates to a paroxetine, or a pharmaceutically acceptable Salt, Solvate, method of treating a patient Suffering from depression, clathrate, polymorph, or co-crystal of either of them. comprising the Step of co-administering to a patient in need 0731. Another aspect of the present invention relates to a thereof a therapeutically effective amount of eSZopiclone, or method of treating a patient Suffering from depression, a pharmaceutically acceptable Salt, Solvate, clathrate, poly comprising the Step of co-administering to a patient in need morph, or co-crystal; and a therapeutically effective amount thereofatherapeutically effective amount of a Sedative agent of a norepinephrine reuptake inhibitor; wherein Said nore and a therapeutically effective amount of a Serotonin pinephrine reuptake inhibitor is desipramine, reboxetine, reuptake inhibitor; wherein Said Sedative agent is eSZopi Oxaprotiline, (S,S)-hydroxybupropion, or a pharmaceuti clone or a pharmaceutically acceptable Salt, Solvate, clath cally acceptable Salt, Solvate, clathrate, polymorph, or co rate, polymorph, or co-crystal thereof; and Said Serotonin crystal of any one of them. reuptake inhibitor is fluoxetine or a pharmaceutically accept 0737. Another aspect of the present invention relates to a able Salt, Solvate, clathrate, polymorph, or co-crystal thereof. method of treating a patient Suffering from depression, 0732 Another aspect of the present invention relates to a comprising the Step of co-administering to a patient in need method of treating a patient Suffering from depression, thereof a therapeutically effective amount of a Sedative agent comprising the Step of co-administering to a patient in need and a therapeutically effective amount of a 5-HTA modu thereof a therapeutically effective amount of eSZopiclone or lator; wherein Said Sedative agent is a compound that a pharmaceutically acceptable Salt, Solvate, clathrate, poly modulates the activity of a GABA receptor and has a Kless morph, or co-crystal thereof; and a therapeutically effective than about 300 nM in a GABA-receptor binding assay; and amount of fluoxetine hydrochloride or a pharmaceutically said 5-HT modulator is MDL 100907, SR 46349B, YM acceptable Salt, Solvate, clathrate, polymorph, or co-crystal 992, fananserin, oxazolidine compounds A, phenylindole thereof. compounds A, piperidinyl compounds B, Spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceuti 0733. Another aspect of the present invention relates to a method of treating a patient Suffering from depression, cally acceptable Salt, Solvate, clathrate, polymorph, or co comprising the Step of co-administering to a patient in need crystal of any one of them. thereofatherapeutically effective amount of a Sedative agent 0738. Another aspect of the present invention relates to a and a therapeutically effective amount of a norepinephrine method of treating a patient Suffering from depression, reuptake inhibitor; wherein Said Sedative agent is a com comprising the Step of co-administering to a patient in need pound that modulates the activity of a GABA receptor and thereof a therapeutically effective amount of a Sedative agent has a Kless than about 300 nM in a GABA-receptor binding and a therapeutically effective amount of a 5-HTA modu assay; and Said norepinephrine reuptake inhibitor is lator; wherein Said Sedative agent is racemic Zopiclone, desipramine, maprotiline, lofepramine, reboxetine, Oxapro eSZopiclone, indiplon, Zolpidem, Zaleplon, gabOXadol, or a tiline, feZolamine, tomoxetine, (S,S)-hydroxybupropion, or pharmaceutically acceptable Salt, Solvate, clathrate, poly a pharmaceutically acceptable Salt, Solvate, clathrate, poly morph, or co-crystal of any one of them; and said 5-HT2A morph, or co-crystal of any one of them. modulator is MDL 100907, SR 46349B, YM 992, fan 0734. Another aspect of the present invention relates to a anSerin, oxazolidine compounds A, phenylindole com method of treating a patient Suffering from depression, pounds A, piperidinyl compounds B, Spiroazacyclic com comprising the Step of co-administering to a patient in need pounds C, azacyclic compounds D, or a pharmaceutically thereofatherapeutically effective amount of a Sedative agent acceptable Salt, Solvate, clathrate, polymorph, or co-crystal and a therapeutically effective amount of a norepinephrine of any one of them. reuptake inhibitor, wherein Said Sedative agent is racemic 0739. Another aspect of the present invention relates to a Zopiclone, eSZopiclone, indiplon, Zolpidem, Zaleplon, method of treating a patient Suffering from depression, US 2005/0176680 A1 Aug. 11, 2005 68 comprising the Step of co-administering to a patient in need morph, or co-crystal thereof; and a therapeutically effective thereofatherapeutically effective amount of a Sedative agent amount of bupropion or a pharmaceutically acceptable Salt, and a therapeutically effective amount of a 5-HTA modu Solvate, clathrate, polymorph, or co-crystal thereof. lator; wherein Said Sedative agent is eSZopiclone or a phar 0745) Another aspect of the present invention relates to a maceutically acceptable Salt, Solvate, clathrate, polymorph, method of treating a patient Suffering from depression, or co-crystal thereof; and said 5-HT modulator is MDL comprising the Step of co-administering to a patient in need 100907, SR 46349B, YM 992, fananserin, oxazolidine com thereof a therapeutically effective amount of a Sedative pounds A, phenylindole compounds A, piperidinyl com agent, a therapeutically effective amount of a Serotonin pounds B, Spiroazacyclic compounds C, azacyclic com reuptake inhibitor, and at least one pharmaceutically accept pounds D, or a pharmaceutically acceptable Salt, Solvate, able carrier; wherein Said Sedative agent is a compound that clathrate, polymorph, or co-crystal of any one of them. modulates the activity of a GABA receptor and has a KleSS 0740 Another aspect of the present invention relates to a than about 300 nM in a GABA-receptor binding assay; and method of treating a patient Suffering from depression, Said Serotonin reuptake inhibitor is citalopram, dulloxetine, comprising the Step of co-administering to a patient in need escitalopram, fluoxetine, fluvoxamine, milnacipran, paroX thereof a therapeutically effective amount of eSZopiclone etine, Sertraline, clominpramine, femoxetine, indapline, ala and a therapeutically effective amount of a 5-HTA modu prolclate, cericlamine, ifoxetine, or a pharmaceutically lator; wherein said 5-HT modulator is MDL 100907, SR acceptable Salt, Solvate, clathrate, polymorph, or co-crystal 46349B, YM 992, fananserin, or a pharmaceutically accept of any one of them. able Salt, Solvate, clathrate, polymorph, or co-crystal of any 0746. Another aspect of the present invention relates to a one of them. method of treating a patient Suffering from depression, 0741. Another aspect of the present invention relates to a comprising the Step of co-administering to a patient in need method of treating a patient Suffering from depression, thereof a therapeutically effective amount of a Sedative comprising the Step of co-administering to a patient in need agent, a therapeutically effective amount of a Serotonin thereofatherapeutically effective amount of a Sedative agent reuptake inhibitor, and at least one pharmaceutically accept and a therapeutically effective amount of a dopamine able carrier; wherein Said Sedative agent is racemic Zopi reuptake inhibitor; wherein Said Sedative agent is a com clone, eSZopiclone, indiplon, Zolpidem, Zaleplon, gaboxadol, pound that modulates the activity of a GABA receptor and or a pharmaceutically acceptable Salt, Solvate, clathrate, has a Kless than about 300 nM in a GABA-receptor binding polymorph, or co-crystal of any one of them; and Said assay; and Said dopamine reuptake inhibitor is amineptine, Serotonin reuptake inhibitor is citalopram, dulloxetine, esci bupropion, GBR-12935, venlafaxine, 2B-propanoyl-3?-(4- talopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, tolyl)-tropane, or a pharmaceutically acceptable Salt, Sol Sertraline, clominpramine, femoxetine, indapline, alapro Vate, clathrate, polymorph, or co-crystal of any one of them. lclate, cericlamine, ifoxetine, or a pharmaceutically accept 0742 Another aspect of the present invention relates to a able Salt, Solvate, clathrate, polymorph, or co-crystal of any method of treating a patient Suffering from depression, one of them. comprising the Step of co-administering to a patient in need 0747 Another aspect of the present invention relates to a thereofatherapeutically effective amount of a Sedative agent method of treating a patient Suffering from depression, and a therapeutically effective amount of a dopamine comprising the Step of co-administering to a patient in need reuptake inhibitor, wherein Said Sedative agent is racemic thereof a therapeutically effective amount of a Sedative Zopiclone, eSZopiclone, indiplon, Zolpidem, Zaleplon, agent, a therapeutically effective amount of a Serotonin gaboXadol, or a pharmaceutically acceptable Salt, Solvate, reuptake inhibitor, and at least one pharmaceutically accept clathrate, polymorph, or co-crystal of any one of them; and able carrier; wherein Said Sedative agent is racemic Zopi Said dopamine reuptake inhibitor is amineptine, bupropion, clone, eSZopiclone, or a pharmaceutically acceptable Salt, GBR-12935, venlafaxine, 2B-propanoyl-3?-(4-tolyl)-tro Solvate, clathrate, polymorph, or co-crystal of either of them; pane, or a pharmaceutically acceptable Salt, Solvate, clath and Said Serotonin reuptake inhibitor is fluoxetine, paroxet rate, polymorph, or co-crystal of any one of them. ine, or a pharmaceutically acceptable Salt, Solvate, clathrate, 0743 Another aspect of the present invention relates to a polymorph, or co-crystal of either of them. method of treating a patient Suffering from depression, 0748. Another aspect of the present invention relates to a comprising the Step of co-administering to a patient in need method of treating a patient Suffering from depression, thereofatherapeutically effective amount of a Sedative agent comprising the Step of co-administering to a patient in need and a therapeutically effective amount of a dopamine thereof a therapeutically effective amount of a Sedative reuptake inhibitor; wherein Said Sedative agent is eSZopi agent, a therapeutically effective amount of a Serotonin clone or a pharmaceutically acceptable Salt, Solvate, clath reuptake inhibitor, and at least one pharmaceutically accept rate, polymorph, or co-crystal thereof, and Said dopamine able carrier; wherein Said Sedative agent is eSZopiclone or a reuptake inhibitor is amineptine, bupropion, GBR-12935, pharmaceutically acceptable Salt, Solvate, clathrate, poly Venlafaxine, 2,3-propanoyl-3?-(4-tolyl)-tropane, or a phar morph, or co-crystal thereof, and Said Serotonin reuptake maceutically acceptable Salt, Solvate, clathrate, polymorph, inhibitor is fluoxetine or a pharmaceutically acceptable Salt, or co-crystal of any one of them. Solvate, clathrate, polymorph, or co-crystal thereof. 0744. Another aspect of the present invention relates to a 0749 Another aspect of the present invention relates to a method of treating a patient Suffering from depression, method of treating a patient Suffering from depression, comprising the Step of co-administering to a patient in need comprising the Step of co-administering to a patient in need thereof a therapeutically effective amount of eSZopiclone or thereof a therapeutically effective amount of eSZopiclone or a pharmaceutically acceptable Salt, Solvate, clathrate, poly a pharmaceutically acceptable Salt, Solvate, clathrate, poly US 2005/0176680 A1 Aug. 11, 2005 69 morph, or co-crystal thereof; a therapeutically effective agent, a therapeutically effective amount of a 5-HTA modu amount of fluoxetine hydrochloride or a pharmaceutically lator, and at least one pharmaceutically acceptable carrier; acceptable Salt, Solvate, clathrate, polymorph, or co-crystal wherein Said Sedative agent is a compound that modulates thereof, and at least one pharmaceutically acceptable carrier. the activity of a GABA receptor and has a Kless than about 0750 Another aspect of the present invention relates to a 300 nM in a GABA-receptor binding assay; and said 5-HT2A method of treating a patient Suffering from depression, modulator is MDL 100907, SR 46349B, YM 992, fan comprising the Step of co-administering to a patient in need anSerin, oxazolidine compounds A, phenylindole com thereof a therapeutically effective amount of a Sedative pounds A, piperidinyl compounds B, Spiroazacyclic com agent, a therapeutically effective amount of a norepinephrine pounds C, azacyclic compounds D, or a pharmaceutically reuptake inhibitor, and at least one pharmaceutically accept acceptable Salt, Solvate, clathrate, polymorph, or co-crystal able carrier; wherein Said Sedative agent is a compound that of any one of them. modulates the activity of a GABA receptor and has a KleSS 0755. Another aspect of the present invention relates to a than about 300 nM in a GABA-receptor binding assay; and method of treating a patient Suffering from depression, Said norepinephrine reuptake inhibitor is desipramine, comprising the Step of co-administering to a patient in need maprotiline, lofepramine, reboxetine, Oxaprotiline, feZola thereof a therapeutically effective amount of a Sedative mine, tomoxetine, (S,S)-hydroxybupropion, or a pharma agent, a therapeutically effective amount of a 5-HTA modu ceutically acceptable Salt, Solvate, clathrate, polymorph, or lator, and at least one pharmaceutically acceptable carrier; co-crystal of any one of them. wherein Said Sedative agent is racemic Zopiclone, eSZopi 0751. Another aspect of the present invention relates to a clone, indiplon, Zolpidem, Zaleplon, gaboxadol, or a phar method of treating a patient Suffering from depression, maceutically acceptable Salt, Solvate, clathrate, polymorph, comprising the Step of co-administering to a patient in need or co-crystal of any one of them; and Said 5-HTA modulator thereof a therapeutically effective amount of a Sedative is MDL 100907, SR 46349B, YM 992, fananserin, oxazo agent, a therapeutically effective amount of a norepinephrine lidine compounds A, phenylindole compounds A, piperidi reuptake inhibitor, and at least one pharmaceutically accept nyl compounds B, Spiroazacyclic compounds C, azacyclic able carrier; wherein Said Sedative agent is racemic Zopi compounds D, or a pharmaceutically acceptable Salt, Sol clone, eSZopiclone, indiplon, Zolpidem, Zaleplon, gaboxadol, Vate, clathrate, polymorph, or co-crystal of any one of them. or a pharmaceutically acceptable Salt, Solvate, clathrate, 0756. Another aspect of the present invention relates to a polymorph, or co-crystal of any one of them; and Said method of treating a patient Suffering from depression, norepinephrine reuptake inhibitor is desipramine, mapro comprising the Step of co-administering to a patient in need tiline, lofepramine, reboxetine, Oxaprotiline, feZolamine, thereof a therapeutically effective amount of a Sedative tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically agent, a therapeutically effective amount of a 5-HTA modu acceptable Salt, Solvate, clathrate, polymorph, or co-crystal lator, and at least one pharmaceutically acceptable carrier; of any one of them. wherein Said Sedative agent is eSZopiclone or a pharmaceu 0752 Another aspect of the present invention relates to a tically acceptable Salt, Solvate, clathrate, polymorph, or method of treating a patient Suffering from depression, co-crystal thereof; and said 5-HT modulator is MDL comprising the Step of co-administering to a patient in need 100907, SR 46349B, YM992, fananserin, oxazolidine com thereof a therapeutically effective amount of a Sedative pounds A, phenylindole compounds A, piperidinyl com agent, a therapeutically effective amount of a norepinephrine pounds B, Spiroazacyclic compounds C, azacyclic com reuptake inhibitor, and at least one pharmaceutically accept pounds D, or a pharmaceutically acceptable Salt, Solvate, able carrier; wherein Said Sedative agent is eSZopiclone or a clathrate, polymorph, or co-crystal of any one of them. pharmaceutically acceptable Salt, Solvate, clathrate, poly 0757. Another aspect of the present invention relates to a morph, or co-crystal thereof, and Said norepinephrine method of treating a patient Suffering from depression, reuptake inhibitor is desipramine, maprotiline, lofepramine, comprising the Step of co-administering to a patient in need reboxetine, Oxaprotiline, fezolamine, tomoxetine, (S,S)-hy thereof a therapeutically effective amount of eSZopiclone, or droxybupropion, or a pharmaceutically acceptable Salt, Sol a pharmaceutically acceptable Salt, Solvate, clathrate, poly Vate, clathrate, polymorph, or co-crystal of any one of them. morph, or co-crystal of any one of them; a therapeutically 0753. Another aspect of the present invention relates to a effective amount of a 5-HTA modulator; and at least one method of treating a patient Suffering from depression, pharmaceutically acceptable carrier; wherein Said 5-HT2A comprising the Step of co-administering to a patient in need modulator is MDL 100907, SR 46349B, YM 992, fan thereof a therapeutically effective amount of eSZopiclone or anSerin, or a pharmaceutically acceptable Salt, Solvate, clath a pharmaceutically acceptable Salt, Solvate, clathrate, poly rate, polymorph, or co-crystal of any one of them. morph, or co-crystal thereof; a therapeutically effective 0758 Another aspect of the present invention relates to a amount of a norepinephrine reuptake inhibitor, and at least method of treating a patient Suffering from depression, one pharmaceutically acceptable carrier; wherein Said nore comprising the Step of co-administering to a patient in need pinephrine reuptake inhibitor is desipramine, reboxetine, thereof a therapeutically effective amount of a Sedative Oxaprotiline, (S,S)-hydroxybupropion, or a pharmaceuti agent, a therapeutically effective amount of a dopamine cally acceptable Salt, Solvate, clathrate, polymorph, or co reuptake inhibitor, and at least one pharmaceutically accept crystal of any one of them. able carrier; wherein Said Sedative agent is a compound that 0754) Another aspect of the present invention relates to a modulates the activity of a GABA receptor and has a KleSS method of treating a patient Suffering from depression, than about 300 nM in a GABA-receptor binding assay; and comprising the Step of co-administering to a patient in need Said dopamine reuptake inhibitor is amineptine, bupropion, thereof a therapeutically effective amount of a Sedative GBR-12935, venlafaxine, 2B-propanoyl-3?-(4-tolyl)-tro US 2005/0176680 A1 Aug. 11, 2005 70 pane, or a pharmaceutically acceptable Salt, Solvate, clath 0765 Another aspect of the present invention relates to a rate, polymorph, or co-crystal of any one of them. method for eliciting a dose sparing effect in a patient 0759 Another aspect of the present invention relates to a undergoing treatment with an antidepressant, comprising the method of treating a patient Suffering from depression, Step of administering to a patient in need thereof, undergoing comprising the Step of co-administering to a patient in need antidepressant therapy, a therapeutically effective amount of thereof a therapeutically effective amount of a Sedative a Sedative agent; wherein Said Sedative agent is a compound agent, a therapeutically effective amount of a dopamine that modulates the activity of a GABA receptor and has a K. reuptake inhibitor, and at least one pharmaceutically accept less than about 300 nM in a GABA-receptor binding assay. able carrier; wherein Said Sedative agent is racemic Zopi 0766. Another aspect of the present invention relates to a clone, eSZopiclone, indiplon, Zolpidem, Zaleplon, gaboxadol, method for eliciting a dose sparing effect in a patient or a pharmaceutically acceptable Salt, Solvate, clathrate, undergoing treatment with an antidepressant, comprising the polymorph, or co-crystal of any one of them; and Said Step of administering to a patient in need thereof, undergoing dopamine reuptake inhibitor is amineptine, bupropion, antidepressant therapy, a therapeutically effective amount of GBR-12935, venlafaxine, 2B-propanoyl-3?-(4-tolyl)-tro a Sedative agent, wherein Said Sedative agent is racemic pane, or a pharmaceutically acceptable Salt, Solvate, clath Zopiclone, eSZopiclone, indiplon, Zolpidem, Zaleplon, rate, polymorph, or co-crystal of any one of them. gaboXadol, or a pharmaceutically acceptable Salt, Solvate, 0760 Another aspect of the present invention relates to a clathrate, polymorph, or co-crystal of any one of them. method of treating a patient Suffering from depression, 0767 Another aspect of the present invention relates to a comprising the Step of co-administering to a patient in need method for eliciting a dose sparing effect in a patient thereof a therapeutically effective amount of a Sedative undergoing treatment with an antidepressant, comprising agent, a therapeutically effective amount of a dopamine administering to the patient in need thereof, undergoing reuptake inhibitor, and at least one pharmaceutically accept antidepressant therapy, a therapeutically effective amount of able carrier; wherein Said Sedative agent is eSZopiclone or a eSZopiclone, or a pharmaceutically acceptable Salt, Solvate, pharmaceutically acceptable Salt, Solvate, clathrate, poly clathrate, polymorph, or co-crystal thereof. morph, or co-crystal thereof, and Said dopamine reuptake 0768 Another aspect of the present invention relates to a inhibitor is amineptine, bupropion, GBR-12935, venlafax method for reducing depression relapse in a patient who ine, 2(3-propanoyl-3?-(4-tolyl)-tropane, or a pharmaceuti received antidepressant treatment, comprising the Step of cally acceptable Salt, Solvate, clathrate, polymorph, or co administering to a patient in need thereof, receiving antide crystal of any one of them. preSSant treatment, a therapeutically effective amount of a 0761. Another aspect of the present invention relates to a Sedative agent, wherein Said Sedative agent is a compound method of treating a patient Suffering from depression, that modulates the activity of a GABA receptor and has a K. comprising the Step of co-administering to a patient in need less than about 300 nM in a GABA-receptor binding assay. thereof a therapeutically effective amount of eSZopiclone or 0769. Another aspect of the present invention relates to a a pharmaceutically acceptable Salt, Solvate, clathrate, poly method for reducing depression relapse in a patient who morph, or co-crystal thereof; and a therapeutically effective received antidepressant treatment, comprising the Step of amount of bupropion or a pharmaceutically acceptable Salt, administering to a patient in need thereof, receiving antide Solvate, clathrate, polymorph, or co-crystal thereof, and at preSSant treatment, a therapeutically effective amount of a least one pharmaceutically acceptable carrier. Sedative agent, wherein Said Sedative agent is racemic 0762. Another aspect of the present invention relates to a Zopiclone, eSZopiclone, indiplon, Zolpidem, Zaleplon, method of augmentation of antidepressant therapy in a gaboXadol, or a pharmaceutically acceptable Salt, Solvate, patient, comprising the Step of administering to a patient in clathrate, polymorph, or co-crystal of any one of them. need thereof, undergoing antidepressant therapy, a therapeu 0770 Another aspect of the present invention relates to a tically effective amount of a Sedative agent, wherein Said method for reducing depression relapse in a patient who Sedative agent is a compound that modulates the activity of received antidepressant treatment, comprising administering a GABA receptor and has a K, less than about 300 nM in a to the patient in need thereof receiving antidepressant treat GABA-receptor binding assay. ment, a therapeutically effective amount of eSZopiclone, or 0763 Another aspect of the present invention relates to a a pharmaceutically acceptable Salt, Solvate, clathrate, poly method of augmentation of antidepressant therapy in a morph, or co-crystal thereof. patient, comprising the Step of administering to a patient in need thereof, undergoing antidepressant therapy, a therapeu 0771. In certain embodiments, the present invention tically effective amount of a Sedative agent, wherein Said relates to the aforementioned method, wherein the eSZopi Sedative agent is racemic Zopiclone, eSZopiclone, indiplon, clone is administered chronically or long-term. Zolpidem, Zaleplon, gaboxadol, or a pharmaceutically 0772 Another aspect of the present invention relates to a acceptable Salt, Solvate, clathrate, polymorph, or co-crystal method for improving the efficacy of antidepressant therapy of any one of them. in a patient Suffering from depression, comprising the Step of 0764. Another aspect of the present invention relates to a administering to a patient in need thereof, undergoing anti method for augmentation of antidepressant therapy in a depressant therapy, a therapeutically effective amount of a patient comprising administering to the patient in need Sedative agent, wherein Said Sedative agent is a compound thereof, undergoing antidepressant therapy, a therapeutically that modulates the activity of a GABA receptor and has a K. effective amount of eSZopiclone, or a pharmaceutically less than about 300 nM in a GABA-receptor binding assay. acceptable Salt, Solvate, clathrate, polymorph, or co-crystal 0773) Another aspect of the present invention relates to a thereof. method for improving the efficacy of antidepressant therapy US 2005/0176680 A1 Aug. 11, 2005 in a patient Suffering from depression, comprising the Step of therapeutic action. These formulations, at comparable daily administering to a patient in need thereof, undergoing anti dosages of conventional immediate release drug, are often depressant therapy, a therapeutically effective amount of a asSociated with a lower incidence or Severity of adverse drug Sedative agent, wherein Said Sedative agent is racemic reactions, and they can also be administered at a lower daily Zopiclone, eSZopiclone, indiplon, Zolpidem, Zaleplon, dose than conventional oral medication while maintaining gaboXadol, or a pharmaceutically acceptable Salt, Solvate, therapeutic activity. clathrate, polymorph, or co-crystal of any one of them. 0782. In certain embodiments, the combination therapy 0774. Another aspect of the present invention relates to a can be formulated to delivery the therapeutic agents at the method for improving the tolerability of antidepressant Same time or at Separate times. In certain embodiments, the therapy in a patient Suffering from depression, comprising first and Second therapeutic agents are administered via an administering to the patient in need thereof, undergoing oral Solid dosage form that includes a Sustained release antidepressant therapy, a therapeutically effective amount of carrier causing the Sustained release of the first therapeutic eSZopiclone, or a pharmaceutically acceptable Salt, Solvate, agent, or both the first therapeutic agent and the Second clathrate, polymorph, or co-crystal thereof. therapeutic agent when the dosage form contacts gas trointestinal fluid. The Sustained release dosage form may 0775 Another aspect of the present invention relates to a comprise a plurality of Substrates which include the drugs. method for improving the tolerability of antidepressant The Substrates may comprise matrix spheroids or may therapy in a patient Suffering from depression, comprising comprise inert pharmaceutically acceptable beads which are the Step of administering to a patient in need thereof, coated with the drugs. The coated beads are then preferably undergoing antidepressant therapy, a therapeutically effec overcoated with a Sustained release coating comprising the tive amount of a Sedative agent, wherein Said Sedative agent Sustained release carrier. The matrix spheroid may include is racemic Zopiclone, eSZopiclone, indiplon, Zolpidem, Zale the Sustained release carrier in the matrix itself, or the matrix plon, gaboxadol, or a pharmaceutically acceptable Salt, may comprise a normal release matrix containing the drugs, Solvate, clathrate, polymorph, or co-crystal of any one of the matrix having a coating applied thereon which comprises them. the Sustained release carrier. In other embodiments, the oral 0776. Another aspect of the present invention relates to a Solid dosage form comprises a tablet core containing the method for improving the tolerability of antidepressant drugs within a normal release matrix, with the tablet core therapy in a patient Suffering from depression, comprising being coated with a Sustained release coating comprising the administering to the patient in need thereof, undergoing Sustained release carrier. In further embodiments, the tablet antidepressant therapy, a therapeutically effective amount of contains the drugs within a Sustained release matrix com eSZopiclone, or a pharmaceutically acceptable Salt, Solvate, prising the Sustained release carrier. In additional embodi clathrate, polymorph, or co-crystal thereof. ments, the tablet contains the first therapeutic agent within a Sustained release matrix and the Second therapeutic agent 0777. In certain embodiments, the present invention coated into the tablet as an immediate release layer. relates to the aforementioned methods, wherein the antide preSSant is citalopram, dulloxetine, escitalopram, fluoxetine, 0783 The term “sustained release” is defined for pur fluvoxamine, milnacipran, paroxetine, Sertraline, clomin poses of the present invention as the release of the thera pramine, femoxetine, indapline, alaprolclate, cericlamine, peutic agent from the formulation at Such a rate that blood ifoxetine, or a pharmaceutically acceptable Salt, Solvate, (e.g., plasma) concentrations (levels) are maintained within clathrate, polymorph, or co-crystal of any one of them. the therapeutic range (above the minimum effective analge sic concentration or “MEAC) but below toxic levels over a 0778 In certain embodiments, the present invention period of time of about 12 hours or longer. relates to the aforementioned methods, wherein the antide 0784 The first and second therapeutic agents can be preSSant is desipramine, maprotiline, lofepramine, reboxet formulated as a controlled or Sustained release oral formu ine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybu lation in any Suitable tablet, coated tablet or multiparticulate propion, or a pharmaceutically acceptable Salt, Solvate, formulation known to those skilled in the art. The Sustained clathrate, polymorph, or co-crystal of any one of them. release dosage form may optionally include a Sustained 0779. In certain embodiments, the present invention released carrier which is incorporated into a matrix along relates to the aforementioned methods, wherein the antide with the active agents, or which is applied as a Sustained preSSant is a dopamine reuptake inhibitor or an atypical release coating. antidepressant. 0785. The sustained release dosage form may include the 0780. Immediate/Sustained Release Combination first therapeutic agent in Sustained release form and Second Therapy Dosage Forms therapeutic agent in the Sustained release form or in imme diate release form. The first therapeutic agent may be 0781. The combination therapy may be formulated in an incorporated into the Sustained release matrix along with the immediate release dosage form or a Sustained release dosage Second therapeutic agent, incorporated into the Sustained form. In certain embodiments, the present invention relates release coating, incorporated as a separated Sustained release to immediate release dosage forms of the first and Second layer or immediate release layer, or may be incorporated as therapeutic agents. An immediate release dosage form may a powder, granulation, etc., in a gelatin capsule with the be formulated as a tablet or multiparticulate which may be Substrates of the present invention. Alternatively, the Sus encapsulated. Other immediate release dosage forms known tained release dosage form may have the first therapeutic in the art can be employed. In certain embodiments, the agent in the Sustained release form and the Second thera combination of therapeutic agents may be formulated to peutic agent in the Sustained release form or immediate provide for an increased duration (Sustained release) of release form. US 2005/0176680 A1 Aug. 11, 2005 72

0786) An oral dosage form according to the invention impart a repeat-action effect whereby unprotected drug is may be provided as, for example, granules, Spheroids, beads, coated over the enteric coat and is released in the Stomach, pellets (hereinafter collectively referred to as “multiparticu while the remainder, being protected by the enteric coating, lates”) and/or particles. An amount of the multiparticulates is released further down the gastrointestinal tract. Coatings which is effective to provide the desired dose of the thera which are pH-dependent may be used in accordance with the peutic agents over time may be placed in a capsule or may present invention include Shellac, cellulose acetate phthalate be incorporated in any other Suitable oral Solid form. In one (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropy certain embodiments of the present invention, the Sustained lmethylcellulose phthalate, and methacrylic acid ester release dosage form comprises Such particles containing or copolymers, Zein, and the like. Thus, one aspect of the comprising the active ingredient, wherein the particles have present invention relates to a formulation wherein the first diameter from about 0.1 mm to about 2.5 mm, preferably therapeutic agent is coated over the enteric coat and released from about 0.5 mm to about 2 mm. into the Stomach while the Second therapeutic agent is 0787. In certain embodiments, the particles comprise protected by the enteric coating and is released further down normal release matrixes containing the first therapeutic the GI tract. Alternatively, one aspect of the present inven agent with the Second therapeutic agent. These particles are tion relates to a formulation wherein the Second therapeutic then coated with the Sustained release carrier in embodi agent is coated over the enteric coat and released into the ments where the first therapeutic agent is immediately Stomach while the first therapeutic agent is protected by the released, the first therapeutic agent may be included in enteric coating and is released further down the GI tract. Separate normal release matrix particles, or may be co 0792. In certain preferred embodiments, the substrate administered in a different immediate release composition (e.g., tablet core bead, matrix particle) containing the first which is either enveloped within a gelatin capsule or is therapeutic agent (with or without the Second therapeutic administered Separately. In other embodiments, the particles agent) is coated with a hydrophobic material Selected from comprise inert beads which are coated with the Second (i) an alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures therapeutic agent with the first therapeutic agents. Thereaf thereof. The coating may be applied in the form of an ter, a coating comprising the Sustained release carrier is organic or aqueous Solution or dispersion. The coating may applied onto the beads as an overcoat. be applied to obtain a weight gain from about 2 to about 25% of the Substrate in order to obtain a desired Sustained release 0788. The particles are preferably film coated with a profile. Alternatively, the invention relates to instances material that permits release of the active agents at a wherein the Substrate (e.g., tablet core bead, matrix particle) Sustained rate in an aqueous medium. The film coat is chosen containing the Second therapeutic agent (with or without the So as to achieve, in combination with the other Stated first therapeutic agent) is coated with a hydrophobic mate properties, a desired in Vitro release rate. The Sustained rial. Such formulations are described, e.g., in detail in U.S. release coating formulations of the present invention should Pat. Nos. 5,273,760 and 5,286,493. Other examples of be capable of producing a strong, continuous film that is Sustained release formulations and coatings which may be Smooth and elegant, capable of Supporting pigments and used in accordance with the present invention include U.S. other coating additives, non-toxic, inert, and tack-free. Pat. Nos. 5,324,351; 5,356,467, and 5,472,712. 0789 Coatings 0793 Alkylcellulose Polymers 0790 The dosage forms of the present invention may 0794. Cellulosic materials and polymers, including alky optionally be coated with one or more materials Suitable for lcelluloses, provide hydrophobic materials well Suited for the regulation of release or for the protection of the formu coating the formulations according to the invention. Simply lation. In one embodiment, coatings are provided to permit by way of example, one preferred alkylcellulosic polymer is either pH-dependent or pH-independent release, e.g., when ethylcellulose, although the artisan will appreciate that other exposed to gastrointestinal fluid. A pH-dependent coating cellulose and/or alkylcellulose polymers may be readily Serves to release the first active agent, Second active agent, employed, Singly or in any combination, as all or part of a or both in the desired areas of the gastro-intestinal (GI) tract, hydrophobic coating. e.g., the Stomach or Small intestine, Such that an absorption profile is provided which is capable of providing at least 0795 One commercially-available aqueous dispersion of about twelve hours and preferably up to twenty-four hours ethylcellulose is Aquacoat(R) (FMC Corp., Philadelphia, Pa., of therapeutic benefit to a patient. When a pH-independent U.S.A.). Aquacoat(R) is prepared by dissolving the ethylcel coating is desired, the coating is designed to achieve optimal lulose in a water-immiscible organic Solvent and then emul release regardless of pH-changes in the environmental fluid, Sifying the Same in water in the presence of a Surfactant and e.g., the GI tract. It is also possible to formulate composi a Stabilizer. After homogenization to generate Submicron tions which release a portion of the dose in one desired area droplets, the organic Solvent is evaporated under vacuum to of the GI tract, e.g., the Stomach, and release the remainder form a pseudolateX. The plasticizer is not incorporated in the of the dose in another area of the GI tract, e.g., the Small pseudolateX during the manufacturing phase. Thus, prior to intestine. In certain embodiments, the first therapeutic agent using the same as a coating, it is necessary to intimately mix is released in one area of the GI tract and the Second the Aquacoat(E) with a Suitable plasticizer prior to use. therapeutic agent is released in a Second area of the GI tract. 0796 Another aqueous dispersion of ethylcellulose is In certain embodiments, the first and Second therapeutic commercially available as Surelease(R) (Colorcon, Inc., West agents are released in nearly equal amounts at the same Point, Pa., U.S.A.). This product is prepared by incorporat location in the GI tract. ing plasticizer into the dispersion during the manufacturing 0791) Formulations according to the invention that utilize process. A hot melt of a polymer, plasticizer (dibutyl Seba pH-dependent coatings to obtain formulations may also cate), and Stabilizer (oleic acid) is prepared as a homoge US 2005/0176680 A1 Aug. 11, 2005 73 neous mixture, which is then diluted with an alkaline Solu order to ultimately obtain a Sustained release formulation tion to obtain an aqueous dispersion which can be applied having a desirable dissolution profile. Desirable Sustained directly onto Substrates. release formulations may be obtained, for instance, from a retardant coating derived from 100% Eudragit R. RL, 50% 0797 Acrylic Polymers Eudragit(R) RL and 50% Eudragit(R) RS, and 10% Eudragit(R) 0798. In other preferred embodiments of the present RL: EudragitE 90% RS. Of course, one skilled in the art will invention, the hydrophobic material comprising the con recognize that other acrylic polymerS may also be used, Such trolled release coating is a pharmaceutically acceptable as, for example, Eudragit(R) L. acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copoly 0803) Plasticizers mers, ethoxyethyl methacrylates, cyanoethyl methacrylate, 0804. In embodiments of the present invention where the poly(acrylic acid), poly(methacrylic acid), methacrylic acid coating comprises an aqueous dispersion of a hydrophobic alkylamide copolymer, poly(methyl methacrylate), poly material, the inclusion of an effective amount of a plasticizer methacrylate, poly(methyl methacrylate) copolymer, poly in the aqueous dispersion of hydrophobic material will acrylamide, aminoalkyl methacrylate copolymer, poly further improve the physical properties of the Sustained (methacrylic acid anhydride), and glycidyl methacrylate release coating. For example, because ethylcellulose has a copolymers. relatively high glass transition temperature and does not 0799. In certain preferred embodiments, the acrylic poly form flexible films under normal coating conditions, it is mer is comprised of one or more ammonio methacrylate preferable to incorporate a plasticizer into an ethylcellulose copolymers. Ammonio methacrylate copolymers are well coating containing Sustained release coating before using the known in the art, and are copolymers of acrylic and meth Same as a coating material. Generally, the amount of plas acrylic acid esters with a low content of quaternary ammo ticizer included in a coating Solution is based on the con nium groups. In order to obtain a desirable dissolution centration of the film-former, e.g., most often from about 1 profile, it may be necessary to incorporate in a coating two to about 50 percent by weight of the film-former. Concen or more ammonio methacrylate copolymers having differing tration of the plasticizer, however, can only be properly physical properties, Such as different molar ratioS of the determined after careful experimentation with the particular quaternary ammonium groups to the neutral (meth)acrylic coating Solution and method of application. eSterS. 0805 Examples of suitable plasticizers for ethylcellulose 0800 Certain methacrylic acid ester-type polymers are include water insoluble plasticizerS Such as dibutyl sebacate, useful for preparing pH-dependent coatings which may be diethyl phthalate, triethylcitrate, tributyl citrate, and triace used in accordance with the present invention. For example, tin, although it is possible that other water-insoluble plasti there are a family of copolymerS Synthesized from diethy cizers (Such as acetylated monoglycerides, phthalate esters, laminoethyl methacrylate and other neutral methacrylic castor oil, etc.) may be used. Triethylcitrate is an especially esters, also known as methacrylic acid copolymer or poly preferred plasticizer for the aqueous dispersions of ethyl meric methacrylates, commercially available as EudragitE) cellulose of the present invention. from Rohm Tech, Inc. There are several different types of 0806 Examples of suitable plasticizers for the acrylic Eudragit(R). For example, EudragitE E is an example of a polymers of the present invention include, but are not methacrylic acid copolymer which Swells and dissolves in limited to citric acid esters such as triethylcitrate NF XVI, acidic media. Eudragit(R) L is a methacrylic acid copolymer tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene which does not Swell at about pH-5.7 and is soluble at about glycol. Other plasticizers which have proved to be suitable pH>6. EudragitES does not swell at about pH-6.5 and is for enhancing the elasticity of the films formed from acrylic soluble at about pH>7. Eudragit(R) RL and Eudragit(R) RS are films such as EudragitE) RL/RS lacquer Solutions include water Swellable, and the amount of water absorbed by these polyethylene glycols, propylene glycol, diethyl phthalate, polymers is pH-dependent, however, dosage forms coated castor oil, and triacetin. Triethyl citrate is an especially with Eudragit R. RL and RS are pH-independent. preferred plasticizer for the aqueous dispersions of ethyl 0801. In certain preferred embodiments, the acrylic coat cellulose of the present invention. ing comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the 0807. It has further been found that the addition of a small Tradenames Eudragit(R) RL30D and Eudragit(R) RS30D, amount of talc reduces the tendency of the aqueous disper respectively. Eudragit(R) RL30D and Eudragit R RS30D are Sion to Stick during processing, and acts as a polishing agent. copolymers of acrylic and methacrylic esters with a low 0808 Processes for Preparing Coated Beads content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic 0809. When the aqueous dispersion of hydrophobic esters being 1:20 in Eudragit(R) RL30D and 1:40 in material is used to coat inert pharmaceutical beads Such as EudragitE RS30D. The mean molecular weight is about nu pariel 18/20 beads, a plurality of the resultant stabilized 150,000. The code designations RL (high permeability) and Solid controlled release beads may thereafter be placed in a RS (low permeability) refer to the permeability properties of gelatin capsule in an amount Sufficient to provide an effec these agents. Eudragit(R) RL/RS mixtures are insoluble in tive controlled release dose when ingested and contacted by water and in digestive fluids. However, coatings formed an environmental fluid, e.g., gastric fluid or dissolution from the same are Swellable and permeable in aqueous media. Solutions and digestive fluids. 0810) The stabilized controlled release bead formulations 0802. The Eudragit R. RL/RS dispersions of the present of the present invention slowly release the therapeutically invention may be mixed together in any desired ratio in active agent, e.g., when ingested and exposed to gastric US 2005/0176680 A1 Aug. 11, 2005 74 fluids, and then to intestinal fluids. The controlled release Spray equipment known in the art. In a preferred method, a profile of the formulations of the invention can be altered, Wurster fluidized-bed system is used in which an air jet, for example, by varying the amount of Overcoating with the injected from underneath, fluidizes the core material and aqueous dispersion of hydrophobic material, altering the effects drying while the acrylic polymer coating is sprayed manner in which the plasticizer is added to the aqueous on. A Sufficient amount of the aqueous dispersion of hydro dispersion of hydrophobic material, by varying the amount phobic material to obtain a predetermined controlled release of plasticizer relative to hydrophobic material, by the inclu of Said therapeutically active agent when said coated Sub Sion of additional ingredients or excipients, by altering the Strate is exposed to acqueous Solutions, e.g., gastric fluid, is method of manufacture, etc. The dissolution profile of the preferably applied, taking into account the physical charac ultimate product may also be modified, for example, by teristics of the therapeutically active agent, the manner of increasing or decreasing the thickness of the retardant coat incorporation of the plasticizer, etc. After coating with the Ing. hydrophobic material, a further overcoat of a film-former, Such as Opadry(E), is optionally applied to the beads. This 0811) Spheroids or beads coated with a therapeutically overcoat is provided, if at all, in order to Substantially reduce active agent are prepared, e.g., by dissolving the therapeu agglomeration of the beads. tically active agent in water and then Spraying the Solution onto a Substrate, for example, nu pariel 18/20 beads, using 0815. The release of the therapeutically active agent from a Wuster insert. Optionally, additional ingredients are also the controlled release formulation of the present invention added prior to coating the beads in order to assist the binding can be further influenced, i.e., adjusted to a desired rate, by of the active agents to the beads, and/or to color the Solution, the addition of one or more release-modifying agents, or by etc. For example, a product which includes hydroxypropy providing one or more passageways through the coating. lmethylcellulose, etc. with or without colorant (e.g., The ratio of hydrophobic material to water soluble material Opadry(E), commercially available from Colorcon, Inc.) may is determined by, among other factors, the release rate be added to the Solution and the Solution mixed (e.g., for required and the Solubility characteristics of the materials about 1 hour) prior to application of the same onto the beads. Selected. The resultant coated Substrate, in this example beads, may then be optionally overcoated with a barrier agent, to Sepa 0816. The release-modifying agents which function as rate the therapeutically active agent from the hydrophobic pore-formerS may be organic or inorganic, and include controlled release coating. An example of a Suitable barrier materials that can be dissolved, extracted or leached from agent is one which comprises hydroxypropylmethylcellu the coating in the environment of use. The pore-formers may lose. However, any film-former known in the art may be comprise one or more hydrophilic materials Such as hydrox used. It is preferred that the barrier agent does not affect the ypropylmethylcellulose. dissolution rate of the final product. 0817 The Sustained release coatings of the present inven 0812. The beads may then be overcoated with an aqueous tion can also include erosion-promoting agents Such as dispersion of the hydrophobic material. The aqueous dis Starch and gums. persion of hydrophobic material preferably further includes 0818. The Sustained release coatings of the present inven an effective amount of plasticizer, e.g. triethyl citrate. Pre tion can also include materials useful for making formulated aqueous dispersions of ethylcellulose, Such as microporous lamina in the environment of use, Such as Aquacoat(R) or Surelease(R), may be used. If Surelease(R) is polycarbonates comprised of linear polyesters of carbonic used, it is not necessary to Separately add a plasticizer. acid in which carbonate groups reoccur in the polymer Alternatively, pre-formulated aqueous dispersions of acrylic chain. The release-modifying agent may also comprise a polymerS Such as Eudragit(R) can be used. Semi-permeable polymer. 0813 The coating solutions of the present invention preferably contain, in addition to the film-former, plasticizer, 0819. In certain preferred embodiments, the release and Solvent System (i.e., water), a colorant to provide modifying agent is Selected from hydroxypropylmethylcel elegance and product distinction. Color may be added to the lulose, lactose, metal Stearates, and mixtures of any of the Solution of the therapeutically active agent instead, or in foregoing. addition to the aqueous dispersion of hydrophobic material. 0820) The Sustained release coatings of the present inven For example, color be added to Aquacoat(R) via the use of tion may also include an exit means comprising at least one alcohol or propylene glycol based color dispersions, milled passageway, orifice, or the like. The passageway may be aluminum lakes and opacifierS Such as titanium dioxide by formed by such methods as those disclosed in U.S. Pat. Nos. adding color with Shear to water Soluble polymer Solution 3,845,770; 3,916,889; 4,063,064; and 4,088,864. The pas and then using low shear to the plasticized Aquacoat(R). Sageway can have any shape Such as round, triangular, Alternatively, any Suitable method of providing color to the Square, elliptical, irregular, etc. formulations of the present invention may be used. Suitable ingredients for providing color to the formulation when an 0821 Matrix Bead Formulations aqueous dispersion of an acrylic polymer is used include titanium dioxide and color pigments, Such as iron oxide 0822. In other embodiments of the present invention, the pigments. The incorporation of pigments, may, however, controlled release formulation is achieved via a matrix increase the retard effect of the coating. having a controlled release coating as Set forth above. The present invention may also utilize a controlled release matrix 0814. The plasticized acqueous dispersion of hydrophobic that affords in-vitro dissolution rates of the active agent material may be applied onto the Substrate comprising the within the preferred ranges and that releases the active agent therapeutically active agent by Spraying using any Suitable in a pH-dependent or pH-independent manner. The materials US 2005/0176680 A1 Aug. 11, 2005 75

Suitable for inclusion in a controlled release matrix will 0827. In certain instances, a combination of two or more depend on the method used to form the matrix. hydrophobic materials are included in the matrix formula 0823. For example, a matrix in addition to the first active tions. If an additional hydrophobic material is included, it agent and (optionally) the Second active agent may include: may be Selected from natural and Synthetic waxes, fatty (1) Hydrophilic and/or hydrophobic materials, Such as gums, acids, fatty alcohols, and mixtures of the same. Examples cellulose ethers, acrylic resins, protein derived materials, the include beeSwax, carnauba wax, Stearic acid and Stearyl list is not meant to be exclusive, and any pharmaceutically alcohol. This list is not meant to be exclusive. acceptable hydrophobic material or hydrophilic material 0828 One particular suitable matrix comprises at least which is capable of imparting controlled release of the active one water Soluble hydroxyalkyl cellulose, at least one C2 agent and which melts (or Softens to the extent necessary to Cs, preferably C-C22, aliphatic alcohol and, optionally, at be extruded) may be used in accordance with the present least one polyalkylene glycol. The at least one hydroxyalkyl invention. (2) Digestible, long chain (Cs-Cso, especially cellulose is preferably a hydroxy (C. to C) alkyl cellulose, C-Clio), Substituted or unsubstituted hydrocarbons, Such as Such as hydroxypropylcellulose, hydroxypropylmethylcel fatty acids, fatty alcohols, glyceryl esters of fatty acids, lulose and, especially, hydroxyethylcellulose. The amount of mineral and vegetable oils and waxes, and Stearyl alcohol; the at least one hydroxyalkyl cellulose in the present oral and polyalkylene glycols. dosage form will be determined, inter alia, by the precise 0824. The hydrophobic material is preferably selected rate of release desired for the therapeutic agent. The at least from the group consisting of alkylcelluloses, acrylic and one aliphatic alcohol may be, for example, lauryl alcohol, methacrylic acid polymers and copolymers, shellac, Zein, myristyl alcohol or Stearyl alcohol. In certain embodiments hydrogenated castor oil, hydrogenated vegetable oil, or of the present oral dosage form, however, the at least one mixtures thereof. In certain preferred embodiments of the aliphatic alcohol is cetyl alcohol or cetoStearyl alcohol. The present invention, the hydrophobic material is a pharmaceu amount of the at least one aliphatic alcohol in the present tically acceptable acrylic polymer, including but not limited oral dosage form will be determined, as above, by the to acrylic acid and methacrylic acid copolymers, methyl precise rate of release desired for the therapeutic agent. It methacrylate, methyl methacrylate copolymers, ethoxyethyl will also depend on whether at least one polyalkylene glycol methacrylates, cynaoethyl methacrylate, aminoalkyl meth is present in or absent from the oral dosage form. In the acrylate copolymer, poly(acrylic acid), poly(methacrylic absence of at least one polyalkylene glycol, the oral dosage acid), methacrylic acid alkylamine copolymer, poly(methyl form preferably contains between 20% and 50% (by wt) of methacrylate), poly(methacrylic acid)(anhydride), poly the at least one aliphatic alcohol. When at least one poly methacrylate, polyacrylamide, poly(methacrylic acid anhy alkylene glycol is present in the oral dosage form, then the dride), and glycidyl methacrylate copolymers. In other combined weight of the at least one aliphatic alcohol and the embodiments, the hydrophobic material is Selected from at least one polyalkylene glycol preferably constitutes materials. Such as hydroxyalkylcelluloses Such as hydrox between 20% and 50% (by wt) of the total dosage. ypropylmethylcellulose and mixtures of the foregoing. 0829. In one embodiment, the ratio of, e.g., the at least 0825 Preferred hydrophobic materials are water-in one hydroxyalkyl cellulose or acrylic resin to the at least one Soluble with more or leSS pronounced hydrophilic and/or aliphatic alcohol/polyalkylene glycol determines, to a con hydrophobic trends. Preferably, the hydrophobic materials siderable extent, the release rate of the active agent from the useful in the invention have a melting point from about 30 formulation. A ratio of the at least one hydroxyalkyl cellu to about 200 C., preferably from about 45 to about 90 C. lose to the at least one aliphatic alcohol/polyalkylene glycol Specifically, the hydrophobic material may comprise natural of between 1:2 and 1:4 is preferred, with a ratio of between or Synthetic waxes, fatty alcohols (Such as lauryl, myristyl, 1:3 and 1:4 being particularly preferred. Stearyl, cetyl or preferably cetostearyl alcohol), fatty acids, 0830) The at least one polyalkylene glycol may be, for including but not limited to fatty acid esters, fatty acid example, polypropylene glycolor, which is preferred, poly glycerides (mono-, di-, and tri-glycerides), hydrogenated ethylene glycol. The number average molecular weight of fats, hydrocarbons, normal waxes, Stearic aid, Stearyl alco the at least one polyalkylene glycol is preferred between hol and hydrophobic and hydrophilic materials having 1,000 and 15,000 especially between 1,500 and 12,000. hydrocarbon backbones. Suitable waxes include, for Another Suitable controlled release matrix would comprise example, beeSWax, glycowax, castor wax and carnauba wax. an alkylcellulose (especially ethyl cellulose), a C to C. For purposes of the present invention, a wax-like Substance aliphatic alcohol and, optionally, a polyalkylene glycol. In is defined as any material which is normally Solid at room another preferred embodiment, the matrix includes a phar temperature and has a melting point of from about 30 to maceutically acceptable combination of at least two hydro about 100 C. phobic materials. In addition to the above ingredients, a 0826 Suitable hydrophobic materials which may be used controlled release matrix may also contain Suitable quanti in accordance with the present invention include digestible, ties of other materials, e.g. diluents, lubricants, binders, long chain (Cs-Cso, especially C2-Cao), Substituted or granulating aids, colorants, flavorants and glidants that are unsubstituted hydrocarbons, Such as fatty acids, fatty alco conventional in the pharmaceutical art. hols, glyceryl esters of fatty acids, mineral and vegetable oils and natural and Synthetic waxes. Hydrocarbons having 0831 Pharmaceutical Compositions a melting point of between 25 and 90 C. are preferred. Of the 0832. In another aspect, the present invention provides long chain hydrocarbon materials, fatty (aliphatic) alcohols pharmaceutically acceptable compositions which comprise a are preferred in certain embodiments. The oral dosage form therapeutically-effective amount of one or more of the may contain up to 60% (by weight) of at least one digestible, compounds described above, formulated together with one long chain hydrocarbon. or more pharmaceutically acceptable carriers (additives) US 2005/0176680 A1 Aug. 11, 2005 76 and/or diluents. AS described in detail below, the pharma Such as amino or alkylamino, and are, thus, capable of ceutical compositions of the present invention may be forming pharmaceutically-acceptable Salts with pharmaceu Specially formulated for administration in Solid or liquid tically-acceptable acids. The term "pharmaceutically-ac form, including those adapted for the following: (1) oral ceptable Salts' in this respect, refers to the relatively non administration, for example, drenches (aqueous or non toxic, inorganic and organic acid addition Salts of aqueous Solutions or Suspensions), tablets, e.g., those tar compounds of the present invention. These Salts can be geted for buccal, Sublingual, and Systemic absorption, prepared in Situ in the administration vehicle or the dosage boluses, powders, granules, pastes for application to the form manufacturing process, or by Separately reacting a tongue; (2) parenteral administration, for example, by Sub purified compound of the invention in its free base form with cutaneous, intramuscular, intravenous or epidural injection a Suitable organic or inorganic acid, and isolating the Salt as, for example, a Sterile Solution or Suspension, or SuS thus formed during Subsequent purification. Representative tained-release formulation; (3) topical application, for salts include the hydrobromide, hydrochloride, sulfate, example, as a cream, ointment, or a controlled-release patch bisulfate, phosphate, nitrate, acetate, Valerate, oleate, palmi or spray applied to the skin; (4) intravaginally or intrarec tate, Stearate, laurate, benzoate, lactate, phosphate, tosylate, tally, for example, as a pessary, cream or foam; (5) Sublin citrate, maleate, fumarate, Succinate, tartrate, napthylate, gually; (6) ocularly; (7) transdermally, or (8) nasally. meSylate, glucoheptonate, lactobionate, and laurylsulpho 0833. The phrase “therapeutically-effective amount” as nate salts and the like. (See, for example, Berge et al. (1977) used herein means that amount of a compound, material, or “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19) composition comprising a compound of the present inven 0837. The pharmaceutically acceptable salts of the Sub tion which is effective for producing Some desired thera ject compounds include the conventional nontoxic Salts or peutic effect in at least a Sub-population of cells in an animal quaternary ammonium Salts of the compounds, e.g., from at a reasonable benefit/risk ratio applicable to any medical non-toxic organic or inorganic acids. For example, Such treatment. conventional nontoxic Salts include those derived from inorganic acids Such as hydrochloride, hydrobromic, Sulfu 0834. The phrase “pharmaceutically acceptable” is ric, Sulfamic, phosphoric, nitric, and the like; and the Salts employed herein to refer to those compounds, materials, prepared from organic acids Such as acetic, propionic, Suc compositions, and/or dosage forms which are, within the cinic, glycolic, Stearic, lactic, malic, tartaric, citric, ascorbic, Scope of Sound medical judgment, Suitable for use in contact palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, with the tissues of human beings and animals without benzoic, Salicyclic, Sulfanilic, 2-acetoxybenzoic, fumaric, excessive toxicity, irritation, allergic response, or other toluenesulfonic, methaneSulfonic, ethane disulfonic, oxalic, problem or complication, commensurate with a reasonable isothionic, and the like. benefit/risk ratio. 0838. In other cases, the compounds of the present inven 0835. The phrase “pharmaceutically-acceptable carrier' tion may contain one or more acidic functional groupS and, as used herein means a pharmaceutically-acceptable mate thus, are capable of forming pharmaceutically-acceptable rial, composition or vehicle, Such as a liquid or Solid filler, Salts with pharmaceutically-acceptable bases. The term diluent, excipient, manufacturing aid (e.g., lubricant, talc “pharmaceutically-acceptable Salts' in these instances refers magnesium, calcium or Zinc Stearate, or Steric acid), or to the relatively non-toxic, inorganic and organic base Solvent encapsulating material, involved in carrying or addition Salts of compounds of the present invention. These transporting the Subject compound from one organ, or Salts can likewise be prepared in Situ in the administration portion of the body, to another organ, or portion of the body. vehicle or the dosage form manufacturing process, or by Each carrier must be “acceptable' in the Sense of being Separately reacting the purified compound in its free acid compatible with the other ingredients of the formulation and form with a Suitable base, Such as the hydroxide, carbonate not injurious to the patient. Some examples of materials or bicarbonate of a pharmaceutically-acceptable metal cat which can Serve as pharmaceutically-acceptable carriers ion, with ammonia, or with a pharmaceutically-acceptable include: (1) Sugars, Such as lactose, glucose and Sucrose; (2) organic primary, Secondary or tertiary amine. Representative Starches, Such as corn Starch and potato Starch; (3) cellulose, alkali or alkaline earth Salts include the lithium, Sodium, and its derivatives, Such as Sodium carboxymethyl cellulose, potassium, calcium, magnesium, and aluminum Salts and the ethyl cellulose and cellulose acetate; (4) powdered traga like. Representative organic amines useful for the formation canth; (5) malt, (6) gelatin; (7) talc.; (8) excipients, Such as of base addition Salts include ethylamine, diethylamine, cocoa butter and Suppository waxes; (9) oils, Such as peanut ethylenediamine, ethanolamine, diethanolamine, piperazine oil, cottonseed oil, Safflower oil, Sesame oil, olive oil, corn oil and Soybean oil, (10) glycols, Such as propylene glycol, and the like. (See, for example, Berge et al., Supra) (11) polyols, Such as glycerin, Sorbitol, mannitol and poly 0839 Wetting agents, emulsifiers and lubricants, such as ethylene glycol, (12) esters, such as ethyl oleate and ethyl Sodium lauryl Sulfate and magnesium Stearate, as well as laurate; (13) agar, (14) buffering agents, Such as magnesium coloring agents, release agents, coating agents, Sweetening, hydroxide and aluminum hydroxide; (15) alginic acid, (16) flavoring and perfuming agents, preservatives and antioxi pyrogen-free water, (17) isotonic Saline; (18) Ringer's Solu dants can also be present in the compositions. tion; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) 0840 Examples of pharmaceutically-acceptable antioxi other non-toxic compatible Substances employed in phar dants include: (1) water Soluble antioxidants, such as ascor maceutical formulations. bic acid, cysteine hydrochloride, Sodium bisulfate, Sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble 0836 AS set out above, certain embodiments of the antioxidants, Such as ascorbyl palmitate, butylated present compounds may contain a basic functional group, hydroxyanisole (BHA), butylated hydroxytoluene (BHT), US 2005/0176680 A1 Aug. 11, 2005 77 lecithin, propyl gallate, alpha-tocopherol, and the like; and absorption accelerators, Such as quaternary ammonium com (3) metal chelating agents, such as citric acid, ethylenedi pounds and Surfactants, Such as poloxamer and Sodium amine tetraacetic acid (EDTA), Sorbitol, tartaric acid, phos lauryl Sulfate; (7) wetting agents, Such as, for example, cetyl phoric acid, and the like. alcohol, glycerol monoStearate, and non-ionic Surfactants, 0841 Formulations of the present invention include those (8) absorbents, such as kaolin and bentonite clay; (9) lubri Suitable for oral, nasal, topical (including buccal and Sub cants, Such as talc, calcium Stearate, magnesium Stearate, lingual), rectal, vaginal and/or parenteral administration. Solid polyethylene glycols, Sodium lauryl Sulfate, Zinc Stear The formulations may conveniently be presented in unit ate, Sodium Stearate, Stearic acid, and mixtures thereof, (10) dosage form and may be prepared by any methods well coloring agents, and (11) controlled release agents Such as known in the art of pharmacy. The amount of active ingre croSpoVidone or ethyl cellulose. In the case of capsules, dient which can be combined with a carrier material to tablets and pills, the pharmaceutical compositions may also produce a single dosage form will vary depending upon the comprise buffering agents. Solid compositions of a similar host being treated, the particular mode of administration. type may also be employed as fillers in Soft and hard-shelled The amount of active ingredient which can be combined gelatin capsules using Such excipients as lactose or milk with a carrier material to produce a Single dosage form will Sugars, as well as high molecular weight polyethylene generally be that amount of the compound which produces glycols and the like. a therapeutic effect. Generally, out of one hundred per cent, 0846. A tablet may be made by compression or molding, this amount will range from about 0.1 per cent to about optionally with one or more accessory ingredients. Com ninety-nine percent of active ingredient, preferably from pressed tablets may be prepared using binder (for example, about 5 per cent to about 70 per cent, most preferably from gelatin or hydroxypropylmethyl cellulose), lubricant, inert about 10 per cent to about 30 per cent. diluent, preservative, disintegrant (for example, Sodium 0842) In certain embodiments, a formulation of the Starch glycolate or cross-linked Sodium carboxymethyl cel present invention comprises an excipient Selected from the lulose), Surface-active or dispersing agent. Molded tablets group consisting of cyclodextrins, celluloses, lipoSomes, may be made by molding in a Suitable machine a mixture of micelle forming agents, e.g., bile acids, and polymeric the powdered compound moistened with an inert liquid carriers, e.g., polyesters and polyanhydrides, and a com diluent. pound of the present invention. In certain embodiments, an 0847 The tablets, and other solid dosage forms of the aforementioned formulation renders orally bioavailable a pharmaceutical compositions of the present invention, Such compound of the present invention. as dragees, capsules, pills and granules, may optionally be Scored or prepared with coatings and shells, Such as enteric 0843 Methods of preparing these formulations or com coatings and other coatings well known in the pharmaceu positions include the Step of bringing into association a tical-formulating art. They may also be formulated So as to compound of the present invention with the carrier and, provide slow or controlled release of the active ingredient optionally, one or more accessory ingredients. In general, the therein using, for example, hydroxypropylmethyl cellulose formulations are prepared by uniformly and intimately in varying proportions to provide the desired release profile, bringing into association a compound of the present inven other polymer matrices, lipoSomes and/or microSpheres. tion with liquid carriers, or finely divided Solid carriers, or They may be formulated for rapid release, e.g., freeze-dried. both, and then, if necessary, Shaping the product. They may be Sterilized by, for example, filtration through a 0844. Formulations of the invention suitable for oral bacteria-retaining filter, or by incorporating Sterilizing administration may be in the form of capsules, cachets, pills, agents in the form of Sterile Solid compositions which can be tablets, lozenges (using a flavored basis, usually Sucrose and dissolved in Sterile water, or Some other Sterile injectable acacia or tragacanth), powders, granules, or as a Solution or medium immediately before use. These compositions may a Suspension in an aqueous or non-aqueous liquid, or as an also optionally contain opacifying agents and may be of a oil-in-water or water-in-oil liquid emulsion, or as an elixir or composition that they release the active ingredient(s) only, Syrup, or as pastilles (using an inert base, Such as gelatin and or preferentially, in a certain portion of the gastrointestinal glycerin, or Sucrose and acacia) and/or as mouth washes and tract, optionally, in a delayed manner. Examples of embed the like, each containing a predetermined amount of a ding compositions which can be used include polymeric compound of the present invention as an active ingredient. Substances and waxes. The active ingredient can also be in A compound of the present invention may also be admin micro-encapsulated form, if appropriate, with one or more of istered as a bolus, electuary or paste. the above-described excipients. 0845. In solid dosage forms of the invention for oral 0848. Liquid dosage forms for oral administration of the administration (capsules, tablets, pills, dragees, powders, compounds of the invention include pharmaceutically granules, trouches and the like), the active ingredient is acceptable emulsions, microemulsions, Solutions, Suspen mixed with one or more pharmaceutically-acceptable carri Sions, Syrups and elixirs. In addition to the active ingredient, ers, Such as Sodium citrate or dicalcium phosphate, and/or the liquid dosage forms may contain inert diluents com any of the following: (1) fillers or extenders, Such as monly used in the art, Such as, for example, water or other Starches, lactose, Sucrose, glucose, mannitol, and/or Silicic Solvents, Solubilizing agents and emulsifiers, Such as ethyl acid; (2) binders, Such as, for example, carboxymethylcel alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, lulose, alginates, gelatin, polyvinyl pyrrollidone, Sucrose benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- and/or acacia; (3) humectants, Such as glycerol; (4) disinte butylene glycol, oils (in particular, cottonseed, groundnut, grating agents, Such as agar-agar, calcium carbonate, potato corn, germ, olive, castor and Sesame oils), glycerol, tetrahy or tapioca Starch, alginic acid, certain Silicates, and Sodium drofuryl alcohol, polyethylene glycols and fatty acid esters carbonate; (5) Solution retarding agents, Such as paraffin; (6) of Sorbitan, and mixtures thereof. US 2005/0176680 A1 Aug. 11, 2005 78

0849 Besides inert diluents, the oral compositions can or nonaqueous Solutions, dispersions, Suspensions or emul also include adjuvants Such as wetting agents, emulsifying Sions, or Sterile powders which may be reconstituted into and Suspending agents, Sweetening, flavoring, coloring, per Sterile injectable Solutions or dispersions just prior to use, fuming and preservative agents. which may contain Sugars, alcohols, antioxidants, buffers, 0850. Suspensions, in addition to the active compounds, bacterioStats, Solutes which render the formulation isotonic may contain Suspending agents as, for example, ethoxylated with the blood of the intended recipient or Suspending or isoStearyl alcohols, polyoxyethylene Sorbitol and Sorbitan thickening agents. esters, microcrystalline cellulose, aluminum metahydroxide, 0859 Examples of suitable aqueous and nonaqueous bentonite, agar-agar and tragacanth, and mixtures thereof. carriers which may be employed in the pharmaceutical 0851. Formulations of the pharmaceutical compositions compositions of the invention include water, ethanol, poly of the invention for rectal or vaginal administration may be ols (Such as glycerol, propylene glycol, polyethylene glycol, presented as a Suppository, which may be prepared by and the like), and Suitable mixtures thereof, vegetable oils, mixing one or more compounds of the invention with one or Such as olive oil, and injectable organic esters, Such as ethyl more Suitable nonirritating excipients or carriers comprising, oleate. Proper fluidity can be maintained, for example, by for example, cocoa butter, polyethylene glycol, a Supposi the use of coating materials, Such as lecithin, by the main tory wax or a Salicylate, and which is Solid at room tem tenance of the required particle size in the case of disper perature, but liquid at body temperature and, therefore, will Sions, and by the use of Surfactants. melt in the rectum or vaginal cavity and release the active 0860. These compositions may also contain adjuvants compound. Such as preservatives, wetting agents, emulsifying agents 0852. Formulations of the present invention which are and dispersing agents. Prevention of the action of microor Suitable for vaginal administration also include pessaries, ganisms upon the Subject compounds may be ensured by the tampons, creams, gels, pastes, foams or Spray formulations inclusion of various antibacterial and antifungal agents, for containing Such carriers as are known in the art to be example, paraben, chlorobutanol, phenol Sorbic acid, and the appropriate. like. It may also be desirable to include isotonic agents, Such as Sugars, Sodium chloride, and the like into the composi 0853 Dosage forms for the topical or transdermal admin tions. In addition, prolonged absorption of the injectable istration of a compound of this invention include powders, pharmaceutical form may be brought about by the inclusion Sprays, ointments, pastes, creams, lotions, gels, Solutions, of agents which delay absorption Such as aluminum patches and inhalants. The active compound may be mixed monoStearate and gelatin. under Sterile conditions with a pharmaceutically-acceptable 0861. The therapeutic agent alone or on combination with carrier, and with any preservatives, buffers, or propellants other therapeutic agents can be employed in admixtures with which may be required. conventional excipients, i.e., pharmaceutically acceptable 0854. The ointments, pastes, creams and gels may con organic or inorganic carrier Substances Suitable for oral, tain, in addition to an active compound of this invention, parenteral, nasal, intravenous, Subcutaneous, enteral, or any excipients, Such as animal and vegetable fats, oils, waxes, other Suitable mode of administration, known to the art. paraffins, Starch, tragacanth, cellulose derivatives, polyeth Suitable pharmaceutically acceptable carriers include but ylene glycols, Silicones, bentonites, Silicic acid, talc and Zinc are not limited to water, Salt Solutions, alcohols, gum arabic, oxide, or mixtures thereof. vegetable oils, benzyl alcohols, polyethylene glycols, gelate, 0855 Powders and sprays can contain, in addition to a carbohydrates Such as lactose, amylose or Starch, magne compound of this invention, excipients Such as lactose, talc, sium Stearate talc, Silicic acid, Viscous paraffin, perfume oil, Silicic acid, aluminum hydroxide, calcium Silicates and fatty acid monoglycerides and diglycerides, pentaerythritol polyamide powder, or mixtures of these Substances. SprayS fatty acid esters, hydroxymethylcellulose, polyvinylpyrroli can additionally contain customary propellants, Such as done, etc. The pharmaceutical preparations can be Sterilized and if desired mixed with auxiliary agents, e.g., lubricants, chlorofluorohydrocarbons and volatile unsubstituted hydro preservatives, Stabilizers, wetting agents, emulsifiers, Salts carbons, Such as butane and propane. for influencing osmotic pressure buffers, coloring, flavoring 0856 Transdermal patches have the added advantage of and/or aromatic Substances and the like. They can also be providing controlled delivery of a compound of the present combined where desired with other active agents, e.g., other invention to the body. Such dosage forms can be made by analgesic agents. For parenteral application, particularly dissolving or dispersing the compound in the proper Suitable are oily or aqueous Solutions, as well as Suspen medium. Absorption enhancers can also be used to increase Sions, emulsions, or implants, including Suppositories. the flux of the compound across the skin. The rate of Such Ampoules are convenient unit dosages. For oral application, flux can be controlled by either providing a rate controlling particularly Suitable are tablets, dragees, liquids, drops, membrane or dispersing the compound in a polymer matrix Suppositories, or capsules, caplets and gelcaps. The compo or gel. Sitions intended for oral use may be prepared according to any method known in the art and Such compositions may 0857 Ophthalmic formulations, eye ointments, powders, contain one or more agents Selected from the group con Solutions and the like, are also contemplated as being within Sisting of inert, non-toxic pharmaceutically excipients which the Scope of this invention. are Suitable for the manufacture of tablets. Such excipients 0858 Pharmaceutical compositions of this invention Suit include, for example an inert diluent Such as lactose; granu able for parenteral administration comprise one or more lating and disintegrating agents Such as cornstarch; binding compounds of the invention in combination with one or agents Such as Starch; and lubricating agents Such as mag more pharmaceutically-acceptable Sterile isotonic aqueous nesium Stearate. The tablets may be uncoated or they may be US 2005/0176680 A1 Aug. 11, 2005 79 coated by known techniques for elegance or to delay release amount of a Second therapeutic agent or pharmaceutically of the active ingredients. Formulations for oral use may also acceptable salt thereof which augments the effect of the first be presented as hard gelatin capsules wherein the active therapeutic agent. ingredient is mixed with an inert diluent. 0866. In some cases, in order to prolong the effect of a 0862 Aqueous suspensions contain the above-identified drug, it is desirable to slow the absorption of the drug from combination of drugs and that mixture has one or more Subcutaneous or intramuscular injection. This may be excipients Suitable as Suspending agents, for example phar accomplished by the use of a liquid Suspension of crystalline maceutically acceptable Synthetic gums Such as hydroxypro or amorphous material having poor water Solubility. The rate pylmethylcellulose or natural gums. Oily Suspensions may of absorption of the drug then depends upon its rate of be formulated by Suspending the above-identified combina dissolution which, in turn, may depend upon crystal Size and tion of drugs in a vegetable oil or mineral oil. The oily crystalline form. Alternatively, delayed absorption of a Suspensions may contain a thickening agent Such as beeswax parenterally-administered drug form is accomplished by or cetyl alcohol. A Syrup, elixir, or the like can be used dissolving or Suspending the drug in an oil vehicle. wherein a Sweetened vehicle is employed. Injectable SuS pensions may also be prepared, in which case appropriate 0867 Injectable depot forms are made by forming liquid carriers, Suspending agents and the like may be microencapsule matrices of the Subject compounds in bio employed. It is also possible to freeze-dry the active com degradable polymerS Such as polylactide-polyglycolide. pounds and use the obtained lyophilized compounds, for Depending on the ratio of drug to polymer, and the nature of example, for the preparation of products for injection. the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers 0863. One aspect of combination therapy pertains to a include poly(orthoesters) and poly(anhydrides). Depot method for providing effective therapeutic treatment in injectable formulations are also prepared by entrapping the humans, comprising administering an effective or Sub-thera drug in liposomes or microemulsions which are compatible peutic amount of a first therapeutic agent; and administering with body tissue. an effective amount of a Second therapeutic agent in an amount effective to augment the therapeutic effect provided 0868. When the compounds of the present invention are by Said first therapeutic agent. The Second therapeutic agent administered as pharmaceuticals, to humans and animals, can be administered before, Simultaneously with, or after they can be given perse or as a pharmaceutical composition administration of the first therapeutic agent, as long as the containing, for example, 0.1 to 99% (more preferably, 10 to dosing interval of the Second therapeutic agent overlaps with 30%) of active ingredient in combination with a pharma the dosing interval of the first therapeutic agent (or its ceutically acceptable carrier. therapeutic effect). In other words, according to the method 0869. The preparations of the present invention may be of the present invention, in certain preferred embodiments given orally, parenterally, topically, or rectally. They are of the Second therapeutic agent need not be administered in the course given in forms Suitable for each administration route. Same dosage form or even by the same route of adminis For example, they are administered in tablets or capsule tration as the first therapeutic agent. Rather, the method is form, by injection, inhalation, eye lotion, ointment, Supposi directed to the Surprising Synergistic and/or additive benefits tory, etc. administration by injection, infusion or inhalation; obtained in humans, when therapeutically effective levels of topical by lotion or ointment; and rectal by Suppositories. a first therapeutic agent have been administered to a human, Oral administrations are preferred. and, prior to or during the dosage interval for the Second therapeutic agent or while the human is experiencing the 0870. The phrases “parenteral administration” and therapeutic effect, an effective amount of a Second thera “administered parenterally as used herein means modes of peutic agent to augment the therapeutic effect of the first administration other than enteral and topical administration, therapeutic agent is administered. If the Second therapeutic usually by injection, and includes, without limitation, intra agent is administered prior to the administration of the first venous, intramuscular, intraarterial, intrathecal, intracapSu therapeutic agent, it is preferred that the dosage intervals for lar, intraorbital, intracardiac, intradermal, intraperitoneal, the two drugs overlap, i.e., Such that the therapeutic effect transtracheal, Subcutaneous, Subcuticular, intraarticulare, over at least a portion of the dosage interval of the first Subcapsular, Subarachnoid, intraspinal and intrasternal injec therapeutic agent is at least partly attributable to the Second tion and infusion. therapeutic agent. 0871. The phrases “systemic administration,”“adminis 0864. In an additional method of the invention, the Sur tered Systemically,”“peripheral administration' and “admin prising Synergistic and/or additive benefits obtained in the istered peripherally as used herein mean the administration patient are achieved when therapeutically effective levels of of a compound, drug or other material other than directly the Second therapeutic agent have been administered to the into the central nervous System, Such that it enters the patient, and, during the dosage interval for the Second patient's System and, thus, is Subject to metabolism and therapeutic agent or while the patient is experiencing the other like processes, for example, Subcutaneous administra therapeutic effect by Virtue of the administration of a Second tion. therapeutic agent, an effective amount of a first therapeutic agent to augment the therapeutic effect of the Second thera 0872 These compounds may be administered to humans and other animals for therapy by any Suitable route of peutic agent is administered. administration, including orally, nasally, as by, for example, 0865 Another aspect of combination therapy relates to an a spray, rectally, intravaginally, parenterally, intracisternally oral Solid dosage form comprising an therapeutically effec and topically, as by powders, ointments or drops, including tive amount of a first therapeutic agent together with an buccally and Sublingually. US 2005/0176680 A1 Aug. 11, 2005

0873 Regardless of the route of administration selected, be specially formulated for administration in Solid or liquid the compounds of the present invention, which may be used form, including those adapted for the following: (1) oral in a Suitable hydrated form, and/or the pharmaceutical administration, for example, drenches (aqueous or non compositions of the present invention, are formulated into aqueous Solutions or Suspensions), tablets, boluses, pow pharmaceutically-acceptable dosage forms by conventional ders, granules, pastes for application to the tongue; (2) methods known to those of skill in the art. parenteral administration, for example, by Subcutaneous, intramuscular or intravenous injection as, for example, a 0874) Actual dosage levels of the active ingredients in the Sterile Solution or Suspension; (3) topical application, for pharmaceutical compositions of this invention may be var example, as a cream, ointment or spray applied to the skin, ied So as to obtain an amount of the active ingredient which lungs, or mucous membranes; or (4) intravaginally or is effective to achieve the desired therapeutic response for a intrarectally, for example, as a pessary, cream or foam; (5) particular patient, composition, and mode of administration, Sublingually or buccally; (6) ocularly; (7) transdermally; or without being toxic to the patient. (8) nasally. 0875. The selected dosage level will depend upon a variety of factors including the activity of the particular 0882. The term “treatment” is intended to encompass also compound of the present invention employed, or the ester, prophylaxis, therapy, management and cure. Salt or amide thereof, the route of administration, the time of 0883. The patient receiving this treatment is any animal administration, the rate of excretion or metabolism of the in need, including primates, in particular humans, and other particular compound being employed, the rate and extent of mammals. Such as equines, cattle, Swine and sheep; and absorption, the duration of the treatment, other drugs, com poultry and pets in general. pounds and/or materials used in combination with the par ticular compound employed, the age, Sex, weight, condition, 0884 The compound of the invention can be adminis general health and prior medical history of the patient being tered as Such or in admixtures with pharmaceutically accept able carriers and can also be administered in conjunction treated, and like factors well known in the medical arts. with antimicrobial agents Such as penicillins, cephalospor 0876 A physician or veterinarian having ordinary skill in ins, aminoglycosides and glycopeptides. Conjunctive the art can readily determine and prescribe the effective therapy, thus includes Sequential, Simultaneous and Separate amount of the pharmaceutical composition required. For administration of the active compound in a way that the example, the physician or veterinarian could start doses of therapeutical effects of the first administered one is not the compounds of the invention employed in the pharma entirely disappeared when the Subsequent is administered. ceutical composition at levels lower than that required in 0885. The addition of the active compound of the inven order to achieve the desired therapeutic effect and gradually tion to animal feed is preferably accomplished by preparing increase the dosage until the desired effect is achieved. an appropriate feed premix containing the active compound 0877. In general, a suitable daily dose of a compound of in an effective amount and incorporating the premix into the the invention will be that amount of the compound which is complete ration. the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the 0886 Alternatively, an intermediate concentrate or feed factors described above. Generally, oral, intravenous, intrac Supplement containing the active ingredient can be blended erebroVentricular and Subcutaneous doses of the compounds into the feed. The way in which such feed premixes and of this invention for a patient, when used for the indicated complete rations can be prepared and administered are analgesic effects, will range from about 0.0001 to about 100 described in reference books (such as "Applied Animal mg per kilogram of body weight per day. Nutrition', W. H. Freedman and CO., San Francisco, U.S.A., 1969 or “Livestock Feeds and Feeding O and B books, 0878). If desired, the effective daily dose of the active Corvallis, Ore., U.S.A., 1977). compound may be administered as two, three, four, five, Six or more Sub-doses administered Separately at appropriate 0887 Micelles intervals throughout the day, optionally, in unit dosage 0888 Recently, the pharmaceutical industry introduced forms. Preferred dosing is one administration per day. microemulsification technology to improve bioavailability 0879 While it is possible for a compound of the present of Some lipophilic (water insoluble) pharmaceutical agents. invention to be administered alone, it is preferable to admin Examples include Trimetrine (Dordunoo, S. K., et al., Drug ister the compound as a pharmaceutical formulation (com Development and Industrial Pharmacy, 17(12), 1685-1713, position). 1991 and REV 5901 (Sheen, P. C., et al., J Pharm Sci8O(7), 712-714, 1991). Among other things, microemulsification 0880. The compounds according to the invention may be provides enhanced bioavailability by preferentially directing formulated for administration in any convenient way for use absorption to the lymphatic System instead of the circulatory in human or veterinary medicine, by analogy with other System, which thereby bypasses the liver, and prevents pharmaceuticals. destruction of the compounds in the hepatobiliary circula 0881. In another aspect, the present invention provides tion. pharmaceutically acceptable compositions which comprise a 0889. In one aspect of invention, the formulations contain therapeutically-effective amount of one or more of the micelles formed from a compound of the present invention Subject compounds, as described above, formulated together and at least one amphiphilic carrier, in which the micelles with one or more pharmaceutically acceptable carriers (addi have an average diameter of less than about 100 nm. More tives) and/or diluents. As described in detail below, the preferred embodiments provide micelles having an average pharmaceutical compositions of the present invention may diameter less than about 50 nm, and even more preferred US 2005/0176680 A1 Aug. 11, 2005 embodiments provide micelles having an average diameter ethylacrylamide, and derivatized celluloses Such as less than about 30 nm, or even less than about 20 nm. hydroxymethylcellulose or hydroxyethylcellulose. 0890 While all suitable amphiphilic carriers are contem 0896. In certain embodiments, a formulation of the plated, the presently preferred carriers are generally those present invention comprises a biocompatible polymer that have Generally-Recognized-as-Safe (GRAS) status, and Selected from the group consisting of polyamides, polycar that can both Solubilize the compound of the present inven bonates, polyalkylenes, polymers of acrylic and methacrylic tion and microemulsify it at a later Stage when the Solution esters, polyvinyl polymers, polyglycolides, polysiloxanes, comes into a contact with a complex water phase (Such as one found in human gastro-intestinal tract). Usually, polyurethanes and co-polymers thereof, celluloses, polypro amphiphilic ingredients that Satisfy these requirements have pylene, polyethylenes, polystyrene, polymers of lactic acid HLB (hydrophilic to lipophilic balance) values of 2-20, and and glycolic acid, polyanhydrides, poly(ortho)esters, poly their Structures contain Straight chain aliphatic radicals in the (butic acid), poly(Valeric acid), poly(lactide-co-caprolac range of C-6 to C-20. Examples are polyethylene-glycolized tone), polysaccharides, proteins, polyhyaluronic acids, poly fatty glycerides and polyethylene glycols. cyanoacrylates, and blends, mixtures, or copolymers thereof. 0891 Particularly preferred amphiphilic carriers are satu rated and monounsaturated polyethyleneglycolyzed fatty 0897) Cyclodextrins acid glycerides, Such as those obtained from fully or par tially hydrogenated various vegetable oils. Such oils may 0898 Cyclodextrins are cyclic oligosaccharides, consist advantageously consist of tri- di- and mono-fatty acid glyc ing of 6, 7 or 8 glucose units, designated by the Greek letter erides and di- and mono-polyethyleneglycol esters of the ..alpha., beta. or gamma., respectively. Cyclodextrins with corresponding fatty acids, with a particularly preferred fatty fewer than Six glucose units are not known to exist. The acid composition including capric acid 4-10, capric acid 3-9, glucose units are linked by alpha-1,4-glucosidic bonds. AS a lauric acid 40-50, myristic acid 14-24, palmitic acid 4-14 consequence of the chair conformation of the Sugar units, all and stearic acid 5-15%. Another useful class of amphiphilic Secondary hydroxyl groups (at C-2, C-3) are located on one carriers includes partially esterified Sorbitan and/or Sorbitol, Side of the ring, while all the primary hydroxyl groups at C-6 with saturated or mono-unsaturated fatty acids (SPAN are situated on the other Side. As a result, the external faces series) or corresponding ethoxylated analogs (TWEEN are hydrophilic, making the cyclodextrins water-Soluble. In Series). contrast, the cavities of the cyclodextrins are hydrophobic, since they are lined by the hydrogen of atoms C-3 and C-5, 0892 Commercially available amphiphilic carriers are and by ether-like oxygens. These matrices allow complex particularly contemplated, including Gelucire-Series, Labra ation with a variety of relatively hydrophobic compounds, fil, Labrasol, or Lauroglycol (all manufactured and distrib including, for instance, Steroid compounds Such as 17.beta.- uted by Gattefosse Corporation, Saint Priest, France), PEG estradiol (see, e.g., van Uden et al. Plant CelTiss. Org. Cult. mono-oleate, PEG-di-oleate, PEG-mono-laurate and 38:1-3-113 (1994)). The complexation takes place by Van di-laurate, Lecithin, Polysorbate 80, etc (produced and dis der Waals interactions and by hydrogen bond formation. For tributed by a number of companies in USA and worldwide). a general review of the chemistry of cyclodextrins, See, 0893 Polymers Wenz, Agnew. Chem. Int. Ed. Engl., 33:803-822 (1994). 0894) Hydrophilic polymers suitable for use in the 0899) The physico-chemical properties of the cyclodex present invention are those which are readily water-Soluble, trin derivatives depend Strongly on the kind and the degree can be covalently attached to a vesicle-forming lipid, and of Substitution. For example, their Solubility in water ranges which are tolerated in Vivo without toxic effects (i.e., are from insoluble (e.g., triacetyl-beta-cyclodextrin) to 147% biocompatible). Suitable polymers include polyethylene soluble (w/v) (G-2-beta-cyclodextrin). In addition, they are glycol (PEG), polylactic (also termed polylactide), polyg Soluble in many organic Solvents. The properties of the lycolic acid (also termed polyglycolide), a polylactic-polyg cyclodextrins enable the control over solubility of various lycolic acid copolymer, and polyvinyl alcohol. Preferred formulation components by increasing or decreasing their polymers are those having a molecular weight of from about solubility. 100 or 120 daltons up to about 5,000 or 10,000 daltons, and more preferably from about 300 daltons to about 5,000 0900 Numerous cyclodextrins and methods for their daltons. In a particularly preferred embodiment, the polymer preparation have been described. For example, Parmeter (I), is polyethyleneglycol having a molecular weight of from et al. (U.S. Pat. No. 3,453,259) and Gramera, et al. (U.S. Pat. about 100 to about 5,000 daltons, and more preferably No. 3,459,731) described electroneutral cyclodextrins. having a molecular weight of from about 300 to about 5,000 Other derivatives include cyclodextrins with cationic prop daltons. In a particularly preferred embodiment, the polymer erties Parmeter (II), U.S. Pat. No. 3,453,257), insoluble crosslinked cyclodextrins (Solms, U.S. Pat. No. 3,420,788), is polyethyleneglycol of 750 daltons (PEG(750)). Polymers and cyclodextrins with anionic properties Parmeter (III), may also be defined by the number of monomers therein; a U.S. Pat. No. 3,426,011). Among the cyclodextrin deriva preferred embodiment of the present invention utilizes poly tives with anionic properties, carboxylic acids, phosphorous mers of at least about three monomers, such PEG polymers acids, phosphinous acids, phosphonic acids, phosphoric consisting of three monomers (approximately 150 daltons). acids, thiophosphonic acids, thiosulphinic acids, and Sul 0895 Other hydrophilic polymers which may be suitable fonic acids have been appended to the parent cyclodextrin for use in the present invention include polyvinylpyrroli see, Parmeter (III), Supra). Furthermore, sulfoalkyl ether done, polymethoxazoline, polyethyloxazoline, polyhydrox cyclodextrin derivatives have been described by Stella, et al. ypropyl methacrylamide, polymethacrylamide, polydim (U.S. Pat. No. 5,134,127). US 2005/0176680 A1 Aug. 11, 2005 82

0901 Liposomes hydrophilic polymer into preformed liposomes, Such as by 0902 Liposomes consist of at least one lipid bilayer exposing preformed liposomes to micelles composed of membrane enclosing an aqueous internal compartment. lipid-grafted polymers, at lipid concentrations correspond Liposomes may be characterized by membrane type and by ing to the final mole percent of derivatized lipid which is size. Small unilamellar vesicles (SUVs) have a single mem desired in the liposome. Liposomes containing a hydrophilic brane and typically range between 0.02 and 0.05 um in polymer can also be formed by homogenization, lipid-field diameter; large unilamellar vesicles (LUVS) are typically hydration, or extrusion techniques, as are known in the art. larger than 0.05 um Oligolamellar large vesicles and mul 0908. In another exemplary formulation procedure, the tilamellar vesicles have multiple, usually concentric, mem active agent is first dispersed by Sonication in a lysophos brane layerS and are typically larger than 0.1 um. Liposomes phatidylcholine or other low CMC surfactant (including with Several nonconcentric membranes, i.e., Several Smaller polymer grafted lipids) that readily solubilizes hydrophobic vesicles contained within a larger vesicle, are termed mul molecules. The resulting micellar Suspension of active agent tivesicular vesicles. is then used to rehydrate a dried lipid Sample that contains 0903. One aspect of the present invention relates to a Suitable mole percent of polymer-grafted lipid, or choles formulations comprising liposomes containing a compound terol. The lipid and active agent Suspension is then formed of the present invention, where the liposome membrane is into liposomes using extrusion techniques as are known in formulated to provide a liposome with increased carrying the art, and the resulting liposomes Separated from the capacity. Alternatively or in addition, the compound of the unencapsulated Solution by Standard column Separation. present invention may be contained within, or adsorbed 0909. In one aspect of the present invention, the lipo onto, the liposome bilayer of the liposome. The compound Somes are prepared to have Substantially homogeneous sizes of the present invention may be aggregated with a lipid in a Selected Size range. One effective sizing method Surfactant and carried within the liposome's internal Space; involves extruding an aqueous Suspension of the liposomes in these cases, the liposome membrane is formulated to through a Series of polycarbonate membranes having a resist the disruptive effects of the active agent-Surfactant Selected uniform pore size; the pore size of the membrane aggregate. will correspond roughly with the largest sizes of liposomes 0904. According to one embodiment of the present inven produced by extrusion through that membrane. See e.g., tion, the lipid bilayer of a liposome contains lipids deriva U.S. Pat. No. 4.737,323 (Apr. 12, 1988). tized with polyethylene glycol (PEG), such that the PEG chains extend from the inner Surface of the lipid bilayer into 0910 Release Modifiers the interior Space encapsulated by the liposome, and extend 0911. The release characteristics of a formulation of the from the exterior of the lipid bilayer into the surrounding present invention depend on the encapsulating material, the environment. concentration of encapsulated drug, and the presence of 0905 Active agents contained within liposomes of the release modifiers. For example, release can be manipulated present invention are in Solubilized form. Aggregates of to be pH dependent, for example, using a pH Sensitive Surfactant and active agent (Such as emulsions or micelles coating that releases only at a low pH, as in the Stomach, or containing the active agent of interest) may be entrapped a higher pH, as in the intestine. An enteric coating can be within the interior Space of liposomes according to the used to prevent release from occurring until after passage present invention. A Surfactant acts to disperse and Solubi through the Stomach. Multiple coatings or mixtures of lize the active agent, and may be selected from any Suitable cyanamide encapsulated in different materials can be used to aliphatic, cycloaliphatic or aromatic Surfactant, including obtain an initial release in the Stomach, followed by later but not limited to biocompatible lysophosphatidylcholines release in the intestine. Release can also be manipulated by (LPCs) of varying chain lengths (for example, from about inclusion of Salts or pore forming agents, which can increase C. to about Co). Polymer-derivatized lipids such as PEG water uptake or release of drug by diffusion from the lipids may also be utilized for micelle formation as they will capsule. Excipients which modify the solubility of the drug act to inhibit micelle/membrane fusion, and as the addition can also be used to control the release rate. Agents which of a polymer to surfactant molecules decreases the CMC of enhance degradation of the matrix or release from the matrix the Surfactant and aids in micelle formation. Preferred are can also be incorporated. They can be added to the drug, Surfactants with CMCs in the micromolar range, higher added as a separate phase (i.e., as particulates), or can be CMC surfactants may be utilized to prepare micelles co-dissolved in the polymer phase depending on the com entrapped within liposomes of the present invention, how pound. In all cases the amount should be between 0.1 and ever, micelle Surfactant monomers could affect lipoSome thirty percent (w/w polymer). Types of degradation enhanc bilayer Stability and would be a factor in designing a erS include inorganic Salts. Such as ammonium Sulfate and lipoSome of a desired Stability. ammonium chloride, organic acids Such as citric acid, ben Zoic acid, and ascorbic acid, inorganic baseS Such as Sodium 0906 Liposomes according to the present invention may carbonate, potassium carbonate, calcium carbonate, Zinc be prepared by any of a variety of techniques that are known carbonate, and Zinc hydroxide, and organic bases Such as in the art. See, e.g., U.S. Pat. No. 4,235,871; Published PCT protamine Sulfate, Spermine, choline, ethanolamine, dietha applications WO 96/14057; New RRC, Liposomes: A prac nolamine, and triethanolamine and Surfactants Such as tical approach, IRL Press, Oxford (1990), pages 33-104; Tween(E) and Pluronic(R). Pore forming agents which add Lasic DD, Liposomes from physics to applications, Elsevier microstructure to the matrices (i.e., water Soluble com Science Publishers BV, Amsterdam, 1993. pounds Such as inorganic salts and Sugars) are added as 0907 For example, liposomes of the present invention particulates. The range should be between one and thirty may be prepared by diffusing a lipid derivatized with a percent (w/w polymer). US 2005/0176680 A1 Aug. 11, 2005

0912 Uptake can also be manipulated by altering resi achieve constant release, the individual wax-like Substances dence time of the particles in the gut. This can be achieved, in the formulation should be substantially non-degradable for example, by coating the particle with, or Selecting as the and insoluble in gastrointestinal fluids during the initial encapsulating material, a mucosal adhesive polymer. release phases. Useful water-insoluble wax-like Substances Examples include most polymers with free carboxyl groups, may be those with a water-solubility that is lower than about Such as chitosan, celluloses, and especially polyacrylates (as 1:5,000 (w/w). used herein, polyacrylates refers to polymers including 0.919. In addition to the above ingredients, a sustained acrylate groupS and modified acrylate groupS Such as release matrix may also contain Suitable quantities of other cyanoacrylates and methacrylates). materials, e.g., diluents, lubricants, binders, granulating 0913) Processes for Preparing Matrix-Based Beads aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art. The quantities of these additional 0914. In order to facilitate the preparation of a solid, materials will be sufficient to provide the desired effect to the controlled release, oral dosage form according to this inven desired formulation. In addition to the above ingredients, a tion, any method of preparing a matrix formulation known Sustained release matrix incorporating melt-extruded multi to those skilled in the art may be used. For example particulates may also contain Suitable quantities of other incorporation in the matrix may be effected, for example, by materials, e.g. diluents, lubricants, binders, granulating aids, (a) forming granules comprising at least one water Soluble colorants, flavorants and glidants that are conventional in the hydroxyalkyl cellulose and the active agent; (b) mixing the pharmaceutical art in amounts up to about 50% by weight of hydroxyalkyl cellulose containing granules with at least one the particulate if desired. C.Sub.12 -C.Sub.36 aliphatic alcohol; and (c) optionally, compressing and Shaping the granules. Preferably, the gran 0920 Specific examples of pharmaceutically acceptable ules are formed by wet granulating the hydroxyalkyl cellu carriers and excipients that may be used to formulate oral lose/active agent with water. In a particularly preferred dosage forms are described in the Handbook of Pharmaceu embodiment of this process, the amount of water added tical Excipients, American Pharmaceutical ASSociation during tie wet granulation Step is preferably between 1.5 and (1986). 5 times, especially between 1.75 and 3.5 times, the dry 0921 Melt Extrusion Multiparticulates weight of the active agent. 0922. The preparation of a suitable melt-extruded matrix 0915. In yet other alternative embodiments, a spheroniz according to the present invention may, for example, include ing agent, together with the active ingredient can be spher the Steps of blending the active agent, together with at least onized to form spheroids. Microcrystalline cellulose is pre one hydrophobic material and preferably the additional ferred. A Suitable microcrystalline cellulose is, for example, hydrophobic material to obtain a homogeneous mixture. The the material sold as Avicel PH 101 (Trade Mark, FMC homogeneous mixture is then heated to a temperature Suf Corporation). In Such embodiments, in addition to the active ficient to at least soften the mixture sufficiently to extrude ingredient and Spheronizing agent, the Spheroids may also the same. The resulting homogeneous mixture is then contain a binder. Suitable binders, Such as low Viscosity, extruded to form strands. The extrudate is preferably cooled water soluble polymers, will be well known to those skilled and cut into multiparticulates by any means known in the art. in the pharmaceutical art. However, water Soluble hydroxy The Strands are cooled and cut into multiparticulates. The lower alkyl cellulose, Such as hydroxypropylcellulose, are multiparticulates are then divided into unit doses. The extru preferred. Additionally (or alternatively) the spheroids may date preferably has a diameter of from about 0.1 to about 5 contain a water insoluble polymer, especially an acrylic mm and provides Sustained release of the therapeutically polymer, an acrylic copolymer, Such as a methacrylic acid active agent for a time period of from about 8 to about 24 ethyl acrylate copolymer, or ethyl cellulose. In Such embodi hours. ments, the Sustained release coating will generally include a hydrophobic material Such as (a) a wax, either alone or in 0923. An optional process for preparing the melt extru Sions of the present invention includes directly metering into admixture with a fatty alcohol; or (b) shellac or Zein. an extruder a hydrophobic material, a therapeutically active 0916 Melt Extrusion Matrix agent, and an optional binder, heating the homogenous 0917 Sustained release matrices can also be prepared via mixture; extruding the homogenous mixture to thereby form melt-granulation or melt-extrusion techniques. Generally, Strands, cooling the Strands containing the homogeneous melt-granulation techniques involve melting a normally mixture, cutting the Strands into particles having a size from Solid hydrophobic material, e.g. a wax, and incorporating a about 0.1 mm to about 12 mm; and dividing Said particles powdered drug therein. To obtain a Sustained release dosage into unit doses. In this aspect of the invention, a relatively form, it may be necessary to incorporate an additional continuous manufacturing procedure is realized. hydrophobic Substance, e.g. ethylcellulose or a water-in 0924. The diameter of the extruder aperture or exit port Soluble acrylic polymer, into the molten wax hydrophobic can also be adjusted to vary the thickness of the extruded material. Examples of Sustained release formulations pre Strands. Furthermore, the exit part of the extruder need not pared via melt-granulation techniques are found in U.S. Pat. be round; it can be oblong, rectangular, etc. The exiting No. 4,861,598. Strands can be reduced to particles using a hot wire cutter, 0918. The additional hydrophobic material may comprise guillotine, etc. one or more water-insoluble wax-like thermoplastic Sub 0925. The melt extruded multiparticulate system can be, stances possibly mixed with one or more wax-like thermo for example, in the form of granules, spheroids or pellets plastic Substances being less hydrophobic than Said one or depending upon the extruder exit orifice. For purposes of the more water-insoluble wax-like Substances. In order to present invention, the terms "melt-extruded multiparticu